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Summary
Migraine is a chronic condition of recurrent, throbbing headache generally felt on one side of the head but
can also switch from one side to another. Migraines usually begin in early childhood adolescence or young
adult life. The headache is characteristically accompanied by nausea, vomiting or loss of appetite.
Activity, bright light or loud noises may make the headache worse, so migraineurs often seek out cool,
dark, quiet rooms. Most migraine attacks are lasting from four to 12 hours, although shorter or much
longer headaches can occur. It interferes with the physical ability to function, sometimes requiring bed
rest. Although there are several kinds of migraines, the most common are classic migraine - a migraine
with aura - and common migraine, which has no aura. Migraine attack consists of four phases, namely
prodrome phase, aura phase, headache phase, and postdrome phase. Despite all the suggested hypotheses
of migraine etiology, it remains unknown. Migraine headache is believed to be the result of abnormal
activity in the brain that leads to dilation of the blood vessels on the surface of the brain as well as the
tissues that surround the brain. The dilation of the blood vessels is believed to be associated with
inflammation mechanism. This cerebral/ cranial vasodilation is referred to as “neurogenic inflammation”.
Unfortunately, more is known about the factors involved in the pathophysiology of migraine headache
pain after CNS dysfunction, and not before. In general, the mechanism of migraine attack is believed to
consist of four steps after CNS dysfunction: 1) A local vasodilatation of the intracranial extracerebral
blood vessels / meningeal blood vessel promoted by specific triggers. 2) Stimulation of pain pathways of
the surrounding trigeminal sensory nervous through sensory nerve discharge causing pain impulses to be
transmitted to caudal brain stem nuclei 3) Increased pain response by neuroinflammation process and
release of the vasoactive neuropeptides (CGRP, NK1, and SP). 4) Transportation of pain signals to higher
centers where headache pain is recognized due to trigeminal nerves activation. This in respect, enforces
scientists to test variant sorts of anti- migraines to inhibit the migraine attack in one of the four mentioned
steps. Treatment of migraine could be prophylactic or abortive. Prophylactic anti- migraines are usually
used to reduce the frequencies of headache attacks. They are mostly non- selective drugs and their action
mechanism in migraine is still unknown, which leads to undesired side effects. Abortive anti- migraines
are used to prevent or reduce headache attack in migraine. Based on the pathophysiology of migraine,
scientists believed that the neurotransmitter serotonin (5-HT) is involved in the initiation of the pain in
migraine. These evidence includes the reduction of urinary serotonin and elevation of its major metabolite
5-HIAA during a migraine attack, the sudden and rapid drop of platelet serotonin in addition to the relieve
effect of 5-HT1 agonists. The triptan class of drugs, including sumatriptan, zolmitriptan, eletriptan,
naratriptan, rizatriptan, almotriptan, and frovatriptan constricts the blood vessels by affecting on 5-HT1B/1D
receptors. All triptans are 5-HT1B/1D agonists, they prevent or reduce migraine headache and are very
effective in relieving migraine. However, they do not prevent or reduce the number of attacks of migraine.
In the last ten years, new studies were done to understand the etiology of migraine. The new discovery of
mutations in the calcium channel gene CACNA1A in migraineurs with familial hemiplegic migraine
(FHM) gives link to suggest that migraine (with and without aura) is caused by ion channel abnormalities.
This suggestion is recently supported by identifying a mutation in the potassium channel encoding gene
KCNN3. This gene plays a critical role in determining the firing outline of neurons and acts to regulate
intracellular calcium channels. This potassium channel gene KCNN3 my thus be of pathophysiological
importance in migraine (with and without aura) and in the near future migraine treatments.
Faculty of sciences Division of Medicinal Chemistry
Chapter 1: Targets for drugs action
1.1 Receptors
G- protein- coupled receptors (GPCRs)
1.2 Ion channels
Ligand- gated ion channels
Voltage- gated ion channels
1.3 Enzymes
1.4 Carrier molecules
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A drug is a chemical that affects physiological function in a certain way. Since the 1970s, scientists
discovered that different types of drugs seem to interact in some specificity with different types of target
proteins in the mammalian cells in a way that might modulate their functions. In general, drugs act on four
target proteins in the mammalian cells (figure 1),
namely: 16
- Receptors
- Ion channels
- Enzymes
- Carrier molecules (Transporters)
In this section, we shall focus only on the receptors
and ion channels as main targets for drug actions
related to migraine.
1.1 Receptors
A receptor is a protein molecule that can span the
cellular membrane region to the extracellular
environment. This protein contains an area that faces
the outside of the cell in which a binding site exists
that receives incoming messengers.12 These receptors
binding sites are usually the analogous to the active
site of an enzyme. Considering drugs as chemical
messengers and neurotransmitters that could fit the
binding site and “switch on” the receptor molecule, it
will deliver the message and lead to a biological
effect. Subsequently, other components will be
involved in the transmission of the message, namely
the ion channels and membrane- bound enzymes.12
The drug- receptor interaction that brings about the
conformational change is a combination of lipophilic
attraction, ionic bonding (acid/base) and hydrogen
bonding. Thus, the effectiveness (efficacy) of a drug
to 'switch on' the biochemical steps is dependent upon
these lipophilic and polar interactions; the 'fit'
(affinity) of the compound into the receptor pocket is
dependant upon its three dimensional shape. Usually,
the pharmacological effects of a drug are based on its
chemical structure. Generally, a compound with good
affinity and good efficacy will be a full agonist and
Fig. 1 Types of targets for drug action.
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give the maximum effect at a very low dose. A compound with good affinity and no efficacy will be an
antagonist, i.e. it will elicit its desired pharmacological effect by blocking endogenous mediators. On the
other hand, some drugs are partial agonists and their overall biological effects are a combination of their
affinity and their efficacy.121,122,16
Depending on the structure and the transductions mechanism, there are four receptor types in human
bodies:17
- Ion channel receptors (Ionotropic receptors)
- The G- protein- coupled receptors (GPCRs)
- Kinas- linked receptors
- Nuclear receptors.
Only the first two receptors are involved in the migraine attack, which we shall discuss extensively in the
next sections.
G- Protein coupled receptors (GPCRs)
These metabotropic receptors consist of 7-TM (transmembrane), and have regions exposed both to the
outside and the inside of the cell. In general, this 7-TM,
consists of two binding domains and one G- protein coupling
Binding domains
domain (figure 2).The protein chain winds back and forth
through the cell membrane seven times. Each of the seven
transmembrane sections is hydrophobic and helical in shape.
The N-terminal chain is to the exterior of the cell and is
variable in the length depending on the receptor.
Transmembrane domains are connected by extracellular
loops (EI-III) and intracellular loops (CI-III). 16,17,19
For many years, it is well known that these receptors couple
to intracellular effectors system and have an influence on the
biological activities in our bodies. 12,16 Each GPCR is
G- protein
involved in a different process depending on the coupled
coupling
domain
chemical messenger (neurotransmitters/ hormones). Some
chemical messengers are simple in structure, such as
monoamines (dopamine, histamine, serotonin, acetylcholine,
noradrenaline), others are more complicated, such as Fig. 2 The general structure of GPCRs.
nucleotides, lipids, neuropeptides, peptide hormones, protein
hormones, glycoprotein hormones, glutamate, etc.12 Until now, there are many receptors discovered in the
mammalians; such as NMDA receptors, AMPA receptors, ACh receptors, GABA receptors, 5-HT
receptors, and Purinergic receptors. Some of these receptors were drug targets before being discovered,
others became more interesting after the discovery of their molecular pharmacological importance.
Interestingly, the rate of message transmission via GPCRs is varying. This process is very rapid when it
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involves the synaptic transmission (milliseconds), while it has mediated effects when it involves hormones
of steroid or thyroid which needs hours or days.17 Most of the G- protein coupled receptors (GPCRs) have
at least two conformational states, the inactive- (R) and the active- state (R*), which exist in equilibrium
(figure 3). To promote the activity of these receptors agonists are used, while inverse agonist might reduce
this activity shifting the equilibrium towards (R). An antagonist has no effect on the equilibrium, it
reduces both by competition with other binding ligands. Lately, scientists discovered that some of the
GPCRs are signalling even in the absence of any ligand, the so- called constitutively active GPCRs.122
Inverse
agonist
Agonist
R*
R
Resting
state
RESPONSE
Activated
state
Antagonist
Fig. 3 The two- state model.
It is important here to elucidate briefly the regulation of enzyme coupling and the signal transduction
pathways in GPCRs. Each G-protein consists of a complex of three subunits, namely β- γ, and . The
signal transduction stages depend on the type of G-proteins e.g. Gi- inhibitory, or Gs- stimulatory,
depending on the coupling to the - subunit. Different - subunits have different targets and different
effects. To date, there are four identified - subunits, namely s, i, q, and o. i When a ligand binds to
Gs receptor, the receptor will bind internally to β- γ complex of the Gs protein leaving αs to bind to the
target enzyme and activate it. Conversely, when a ligand binds to an inhibitory receptor it leads to
inactivation of the target enzyme (figure 4).16,17,19
i
 subunits and their functions:
 s stimulates adenylate cyclase; this subunit binds to an enzyme called adenylate cyclase which catalyzed the synthesis
of cyclic AMP(2nd messenger) from ATP. This process required GTP as energy source which is conformed to GDP.
Finally, s –subunit departs the enzyme and recombines with -dimer to reform the Gs protein, which is valid to each
- subunit.
 i inhibits adenylate cyclase; i –subunit does bind to adenylate cyclase and blocked it at the same time, which reduce
the synthesis cAMP. Receptors that can bind Gi-proteins include the muscarinic M2-recptors of cardiac muscle, 2adrenoreceptors in smooth muscle, and opioid receptors in the central nervous system.
 o activates receptors that inhibit neuronal Ca2+ ion channels
 q activates phospholipase C; when q-subunit binds to phospholipase C, the substrate for a membrane-bound
enzyme, phosphatidtylinositol disphosphate (PIP 2), will be hydrolyzed into two second messengers inositol
triphosphate(IP3) and diacylglycerol(DG).
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Fig. 4 GPCRs – ligand regulation.
The main targets for G- proteins are enzymes and ion channels such us adenylate cyclase (AC),
phospholipase C (PC), cGMP phosphodiesterase, and K+ and Ca+2 ion channels. These targets enable
GPCRs to modulate the cellular functions by producing the “second messengers” that has cAMP, IP3, and
DAG inside the cell. cAMP regulates the energy metabolism by activation of protein kinase A (PKA),
while IP3 regulates the ion channels by releasing of Ca+2, and DAG activates protein kinase C (PKC) in
the phosphatidylinositol (PI) cycle (figure 5).16,17
Fig. 5 Signalling pathways arising from the splitting of G- proteins.
In this thesis we shall not consider all these pathways in details. Instead, we shall focus on one pathway,
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namely the activation of adenylate cyclase due to its importance in migraine treatments. When PKA is
activated by cAMP, it will catalyse the phosphorylation of proteins and enzymes at their serine and
threonine residues. This will change the shape of the enzyme leading to the exposure or closure of the
active site and hence will activate the enzyme to perform a specific function, e.g. nuclear phosphorylation
targets include a group of transcription factors that modulate the expression of cAMP- responsive genes.
These factors form a family of both activators and repressors that bind as homo- and heterodimers to
cAMP- responsive elements (CREs). They belong to the basic leucine zipper (bZip) class of transcription
factors, and their function is tightly regulated by phosphorylation. Constitutively expressed factors such as
CREB (CRE- binding protein) are phosphorylated by PKA and thereby converted into transcriptional
activators.135 In fat cells PKA activates enzymes and catalyse the breakdown of fat. Alternatively, it might
have a deactivating effect, which increase lipolysis, decrease the glycogen synthesis, and eventually
increasing the break down of glycogen.17
1.2 Ion channels
Definitely, many cellular functions require the passage of ions and other hydrophilic molecules across the
plasma membrane. Ion channels affect the function of the neurotransmitters, cardiac conductions, and
muscle contractions through the regulation of ion exchange cross the cell.19,21 Recently, experience with
DNA sequence linked many diseases to defects in ion channels “channelopathies”. Plasma membrane ion
channels are often expressed at relatively low concentrations in specific cells and tissues, which make
them easy accessible targets for drug design.23 Basically, there are two groups of ion channels, non- gated
and gated channels26. Non- gated or leakage channels are open even in the unstimulated state. In contrast,
gated ion channels are activated / inactivated in response to specific stimuli. There are two types of gated
channels:19,21,26,56
- Ligand- gated ion channels
- Voltage- gated ion channels
Each type has a different mechanism and activation/ inactivation function regarding its ion selectivity.21
However, they all share some structural similarity. They all tend to be tube- like macromolecules, which
are made of a number of protein subunits that are designed to form water- filled pores pass through the
plasma membrane, and are able to switch between open and closed states.19,21 Usually, the ligand- binding
domain is extracellular (within the channel), or intracellular.21 The selectivity of these ion channels is
strongly dependent on the size of the pore and the nature of its lining.19
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Ligand- gated ion channels
These receptors are able to regulate the ion channels functions, and are also known as ion channels
receptors and ionotropic receptors.17 They are part of five- protein ion channel structure including a
ligand- binding site. They form the extracellular domain of the proteins
There are three known kinds of ionotropic receptors
according to the form of their transmembrane; 2- TM, 3TM, and 4- TM receptors constitute of four to five
subunits.17 One of the major differences between these
three ionotropic receptors is the location of the N- and Cterminal chain (figure 6). 17 There are two kinds of ion
channels; cationic ion channels and anionic ion channels.
Some of the cationic channels are non- selective, while
others select only one of the following cations Na+, K+, or
Ca2+. Anionic channels are primarily permeable to Cl-.17,21
The cationic channels are usually controlled by nACh (4TM) receptors, the 5HT3 (4- TM) receptors, L- glutamate
(3- TM) receptors, and ATP (2- TM) receptors, while the
anionic ion channels are controlled by the GABAA and
glycine receptors.11,17 When the cationic ion channels are
opened, depolarization of the cell takes place and nerve
stimulation occur. In contrast, when the anionic channels
get opened, they will have an inhibitory effect on the
cells.17,16 Interestingly, the selectivity of the ion channels
also depends on the amino acids of these ion channels.
When a mutation in these amino acids occurs, the
selectivity of the ion channels might be changed from
cationic to anionic and vice versa, resulting in
dysregulation of cellular function.17
A) 4-TM
B) 3- TM
C) 2- TM
Voltage- gated ion channels
Ion channels usually consist of five protein subunits, e.g
the ion channels that are controlled by nicotinic
acetylcholine receptor are made of five protein subunits (2
x α, δ, β, γ).17 When the form of the transmembrane is 4TM , each subunit is a tetramic (consists of four Fig. 6 The structure of TM ion channel
receptor subunits
homologous subunits (TM I- IV)) association of a series of
six transmembrane α – helical segments (S1- S6) connected
by both intracellular and extracellular loops (figure 7).24,21,17,56 In voltage- gated calcium and sodium
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channels, the role of α- subunit is very vital, because it determines the characteristics of the complex
assigning ion selectivity such as the regulation of ion- conducting pore, voltage sensors, gates for the
different opened and closed channel states, and binding sites for endogenous and exogenous ligands.24
The transition of the neurotransmitters through the nerves system is usually known as nerves firing and
generation of electrical signal.11,24,21 It is important to mention that the whole process would not happen
without the movement of the ions through ion channels. All cells contain Na+, K+, and Cl-. Potassium ion
channels are expressed in most cell types, they are involved in cell signalling and in the regulation of the
cell membrane potential, which is a key
regulator of many cellular processes.11,23 A) α Subunit comprising four homologous subunits (I-IV)
When the intracellular concentration of K+
is
higher
than
the
extracellular
concentration, and
Cl
and Na+
concentrations are low compared to K+,
ion concentrations gradient across the
membrane
will
exist.
This
ion
concentrations gradient will play a crucial
role in channel gating process. If K+
concentration
moves
down
its
concentration gradient (out of the cell
through the potassium ion channels), an B) Assembled α and auxiliary subunits of a typical voltageelectric potential (50- 80 mV) builds up gated ion channel
across the cell membrane i.e. the inner
membrane layer is more negative than the
outer membrane layer. This will prevent
the continuous flow of K+ to the outside.
In this case, ion channels are in a resting
state. When extra potassium ion channels
are opened, the electric potential across the
cell membrane will be more negative, and
this will destimulate the nerve. This
process is known as hyperpolarization.11
Sodium ion channels are very important Fig. 7 The structure of typical voltage- gated ion channels.
for the transmission of nerve signals.
According to EMBO report,23 some of these sodium ion channels are activated by voltage, while others
are modulated by number of hormones and messengers. Na+ ions have a high tendency to bind its
solvating water molecules than K+, which make it much bigger than the potassium ions.11 Thus, Na+ ions
are not able to exchange with K+ ion in / outside the cells at the same rate. Meanwhile, Na+ channels are
mostly closed when the nerve is in a resting state.11 Consequently, Na+ ions will cross the ion channels
very slowly, leading to an equilibrium (resting potential). Nevertheless, when more Na+ channels are open
depolarization will take place leading to nerve stimulation.11 Finally, nerve destimulation due to
hyperpolarization of the cell membrane will take place again when Cl- channels are opened.11 It is worth to
mention that this depolarization will affect the other ion channels such as Na+/ Ca2+ pump.
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Calcium ions are extruded from the cell in exchange for Na+.25, 21 The exchanger transfers three Na+ for
one Ca2+, leading to a net hyperpolarizing current. Further, Ca2+ - dependent ATPase (Ca2+ pump) will
control the extrusion of Ca+ from the cell, while ligand- gated calcium channels and voltage- gated
calcium channels will control the entry of this cation to the cell.21
1.3 Enzymes
Many of the enzymatic proteins are prime targets for drugs to manipulate cellular functions. Drugs may
act as competitive inhibitors for the enzyme. They could act irreversibly, such as aspirin on
cyclooxygenase or reversibly such as neostigmine on acetylcholinesterase. A well known example of this
useful therapeutic application is the anticancer drug fluorouracil, which blocks DNA synthesis and
prevents cell division by replacing uracil as an intermediate in purine biosynthesis, without converting it
into thymidylate.16
1.4 Carrier molecules
Chemicals such as neurotransmitters and drugs are often very polar, they show insufficient solubility in
lipids, and can not pass through cell membrane without the help of carrier molecules (transporters).16,18,20
These transporters are mostly proteins, but they can also be antibodies. They are very important to
transport ions and small molecules across the cell membranes, including those which are responsible for
the transport of glucose and amino acids into cells and the transport of Na+ and Ca2+ out of the cell and
also the uptake of the neurotransmitters such as 5- hydroxytryptamine (5-HT), glutamate and peptides by
nerve terminals.16 Obviously, these proteins contain a recognition part that is specific for a particular
permeating species. These recognition sides could be used as drug targets that might be blocked by drugs,
which inhibits the transport system and manipulate the cell function such as, cocaine and tricyclic
antidepressants, which block the re- uptake of noradrenaline in nerve synapses, and the famous
antidepressant drug fluoxetine (prozac), which inhibits serotonin uptake selectively.16,18,20
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Chapter 2: Migraine
2.1
Migraine and migraine diagnoses
2.2
Phases of migraine attack
2.2.1 Prodrome phase
2.2.2 Aura phase
2.2.3 Headache phase
2.2.4 Postdrome phase
2.3
Classification
2.4
Migraine triggers
2.5
Migraine theories
2.5.1 Vascular theory
2.5.2 Neurogenic theory
2.5.3 Spreading depression theory
2.5.4 The serotonin dysfunction theory
2.5.5 Unify theory
2.5.6 The neurovascular disorder theory
2.5.7 Other hypothesis
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2.1 Migraine and migraine diagnosis
Through years, headache is classified into two categories according to International Headache Society
(IHS):1
- Primary headache disorder: Tension headache, migraine, cluster, and chronic daily headache.
- Secondary headache disorder: A headache that is caused by meningitis, intracranial hemorrhage, brain
tumor, temporal arteritis, glaucoma, pseudotumor cerebri, malignant hypertension, trauma, or stroke.
Diagnosis of the primary headache disorder should be done after exclusion of the secondary causes of
headache disorder. Migraine is a specific neurological syndrome that has a wide variety of symptoms. 3,5 It
is described as a severe, throbbing headache combined with nausea that might take hours or days.3,5 The
word migraine is initiated from the Latin word “hemicrania”, which Galenii used to describe pain on one
side of the head. Galen hypothesis is that accumulation of bile in the body irritate the intracranial
structures and thus cause headache. Moreover, his theory was that the throbbing pain of migraine occur
due to alternation of blood vessels.1
Migraine symptoms vary significantly among patients, which make it sometimes difficult to diagnose,
especially if patients suffer from more than one type of headache, e.g. tension headache “muscle
contraction headache” in addition to migraine “vascular headache”.1,60 In general, there are specific
symptoms that are associated with migraine attack such us photophobia (sensitivity to light), hyperacusia
(sensitivity to sound), polyuria (the release of abnormally large amounts of urine, adults at least 2.5 L/
day), diarrhea, and visual alternation due to sensory or motor changes.3
The frequency of migraine attack varies from 1-2 times a year to 4 times a month.7,1 Migraine is a
syndrome that affects a substantial fraction of the world’s population, with a higher prevalence in women
(15-18%) than in men (6%).53 The frequency of migraine attack in women is much higher than that in men
due to hormonal changes in women during different periods of life. Studies show that during pregnancy
the migraine attack occur less or might totally disappear, and that a lot of migraineurs suffer from
migraine headache attack shortly before menstruation (menstrual migraine) or even during ovulation. This
was suggested to occur due to drop off the estrogen levels. Noteworthy, migraine might be a factor of
stroke risk, however the cause of stroke during migraine is yet unknown. According to studies done on 22
migraine patients (17 female, 5 meals, and mean age 32.7), it appears that arterial dissection and
vasospasm were not significant causes of stroke during migraine. These patients had longer previous
attacks of migraine and their infarct was more frequent in the territory involved during the attacks than the
controls, supporting the hypothesis that a prolongation of the migrainous process beyond usual limits may
explain most migraine strokes. Additionally, many factors might improve the risk of stroke in migraineurs
such us anticonception pills, smoking, or the combined two factors.57
ii
Galen was a famous physician of the second century [129-c. 199], he was intimately connected with the imperial court when
Christian influence there was on the increase, and was placed in charge of the health of the young Commodus. 131
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Despite all previous studies, the exact nature of the central dysfunction that occurs in migraineurs is still
poorly understood.54,55 Noticeably, more is known about the factors involved in the pathophysiology of
migraine headache pain after CNS dysfunction. In general, scientists believed that migraine patient is
exposed to many migraine triggers that potentially can act at different sites in the cerebral vasculature and
the CNS to promote a local vasodilatation of the intracranial extracerebral blood vessels/ meningeal blood
vessel. The swelled arteries stimulate the surrounding trigeminal sensory nervous pain pathways through
sensory nerve discharge causing pain impulses, to be transmitted to caudal brain stem nuclei. This in turn,
will develop a neuroinflammation process, by which vasoactive neuropeptides will be released, especially
CGRP, NK1 and SP. These neuropeptides increase pain response by increasing the meningeal blood vessel
diameter.54,55 The activation of trigeminal nerves is believed to convey nociceptive information to central
neurons in the brain stem trigeminal sensory nuclei, which consecutively send the pain signals to higher
centers where headache pain is recognized as one of migraine symptoms.54,55 Furthermore, the other
associated migraine symptoms such as phono-, photophobia and nausea are produced when other related
central nuclei and pathways are activated.
Moreover, vasopressin hormone is not responsible in migraine initiation. Vasopressin is a vasoactive
hormone secreted from the posterior pituitary. At low concentration, it regulates renal water excretion
(antidiuretic hormone), while at higher concentrations it has a number of extrarenal actions, including
effects on blood flow. Scientists suggested that vasopressin rises during an attack of spontaneous
migraine, which may be related to emesis. However, release of vasopressin may be responsible for the
facial pallor and antidiuresis observed in some migraineurs.146,147
In the coming sections, the theories of migraine mechanisms and triggers that have been introduced
through years will be presented (see pages 16- 20).
2.2 Migraine animal models
Different studies were done to investigate migraine and anti- migraine agents including the measurement
of cerebral blood flow. Using anesthetized pigs and cats, appropriate catheterization can permit the
measurement of arterial blood pressure and carotid blood flow. The distribution of carotid blood flow can
be determined with radiolabeled microspheres injected into the carotid artery. After removing the tissues
and determining the radioactivity of microspheres, the fraction of carotid blood flow can be calculated by
knowing the ratio of tissue and total radioactivity measurements and common carotid blood flow. As an
index of the arteriovenous anastomotic fraction of carotid blood flow, the amount of radioactivity in lungs
is usually used.142,143
On the other hand, electrical and pharmacological stimulations were applied to investigate the dural
inflammation and the dural extravasation respectively. The electrical stimulations were useful to predict
the clinical activity for serotonergic receptor agonists. In these studies, the inflammation of the neurogenic
dural of anesthetized rats, cats, and guinea pigs was investigated using utilizing unilateral electrical
stimulation of the trigeminal ganglion. For this purpose stereotaxically- placed electrodes and intravenous
injection of fluorescent or radiolabeled proteins were used. These stimulations seem to initiate an
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ipsilateral release of inflammatory neuropeptides such as CGRP, NK1, and SP from the primary sensory
afferents in the dural. This will trigger leakage of labeled plasma proteins (extravasation) into dural tissue.
Interestingly, the ratio of labeled proteins trapped in dural tissue from the stimulated side seems to be the
double to that from the non- stimulated side. This model is widely used to examine the in vivo
effectiveness of many of the suggested anti- migraine agents, although the predictive ability of this model
is limited by species and pharmacokinetic issues.64
Furthermore, meta- chlorophenylpiperazine (mCPP), a nonspecific 5-HT receptor agonist was used in the
pharmacological stimulations. mCPP induces a severe headache- like symptoms in migraineurs due to its
effect on 5-HT2B receptors. This in respect stimulates NO release and triggers the release of inflammatory
neuropeptieds such as CGRP and substance P, which could be inhibited by serotonergic anti- migraine
agonists. Intravenous infusion of mCPP followed by administration of a fluorescent dye in anesthetized
guinea pigs showed a remarkably plasma protein extravasation in dural membranes, which provide
another animal model of migraine inflammation (figure 8 ).144,145
Fig. 8 The electrical and pharmacological stimulation in the brain of animal model .
Similar to mCPP, intravenous infusion with nitroglycerin, a known NO donor, seems to trigger dural
extravasation in guinea pigs. Both, NO and mCPP stimulate neurogenic inflammation which proposed to
mediate the cascade of events triggering migraine pain. However, nitroglycerine- induced dural
extravasation is not related by 5-HT2B receptor antagonists since these receptor antagonists would only
inhibit the endogenouse NO release without blocking the actions of NO. To conclusion, the NO animal
model of migraine provides useful information to detect anti- migraine agents which act at multiple sites
in the sequel of events leading to dural extravasation.144
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2.3 Phases of migraine attack
Noticeably, migraine attack consists of four phases, namely prodrome phase, aura phase, headache phase,
and postdrome phase (figure 9).1,3,4,5,6
Fig. 9 Symptoms and signs during phases of "Complete" migraine attacks with aura.
2.3.1 Prodrome phase:
It is a forewarning phase that might occur 24 hours before the throbbing headache.3,1 In this phase,
changes in mood and appetite are observed, such us irritability, yawning, food cravings, depression, and
other non specific symptoms.1
2.3.2 Aura phase
There are two main types of migraine; the classic (migraine with aura) and the common (migraine without
aura).4,1 A third type of migraine is known as complicated migraine, which seams to share the same
symptoms of classic migraine in addition to double vision and even loss of consciousness, but the pain
will be located in the lower part of the brain or brainstem. This type is mostly diagnosed in teenaged girls.7
In case of common migraine, a throbbing headache follows the prodrome phase within 24 hours without
occurrence of aura. The aura phase in the classic migraine starts usually within an hour before pain onset;
it might ends with headache or may occur while the patient is a sleep.1,4 Up to now, there are two kinds of
known common aura; the visual and the non- visual aura. The visual aura is described as “heat” rising off
pavement in the summertime, or as water cascading down a window pane or sparkling stars.
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Another description is known as seeing highlighted, zigzag lines around objects or parts of visual field.1
The non- visual auras, such as paresthesia or a tingling sensation, could be presented as weakness or
numbness in an extremity or around the face.1 The aura phase is also called the vasospasm phase, in this
phase vasoconstriction seems to occur resulting in deficiency of blood flow in some parts of the brain.7,121
The vision disorder in some people in this phase could be explained by the blood deficiency in the tissues
of the back side of the brain (the visual area). This makes cells more active electrically, because lacking of
a sufficient energy supply will lead to more trouble in controlling the flow of electrically charged ions and
therefore the tissue becomes hyper-excitable.7
2.3.3 Headache phase
A typical migraine headache begins with mild pain grows to moderate or severe throbbing in character
pain and intensifies by movement, which is combined with nausea and vomiting (sick headache).1,7,8 This
severe pain is building up gradually and located in one side of the cranium and lasts between 4 to 72
hours.1,5 In some patients it starts with “switching sides” until it finally “picks a side”, which is not the
case in the other primary or secondary headache disorders.1 However, “thunderclap” migraines can
happen suddenly leading to onset of severe pain with or without aura.1 In this phase, the arteries dilate
excessively after constriction in the aura phase.2,7 Migraineurs suffer from severe pulse headache as the
pulse beat goes through a dilated sensitive artery.7 Those cranial sensitive arteries are pain sensitive
structures in which the walls contain tiny nerve ending that go into the trigeminal nerve.7 After that, the
pain become more diffuse and the inflammatory chemicals and cells ( white cells) will accumulate into
the nervous system covering the brain in an inflammation- muscle contraction stage. During the headache
phase, the person might experience photophobia, hyperacusia, and muscle tenderness in the head and
neck, in addition to autonomic disruption and clouding thoughts or mental functioning that might prolongs
to persistent misery.7,8 All these symptoms are severe enough to introduce disability which force the
patient to confine to bed.7
2.3.4 Postdrome phase
The also called “recovery phase” is characterized by exhaustion, dizziness, and irritability. This phase can
take 48 hours or more.1,5 Migraineurs might have sick stomach, food intolerance, decrease of
concentration, occasional cognitive difficulties, and sore muscles. On the other hand, migraine patient
might experience euphoria and sense of well- being during this phase.8
2.4 Classification
Migraine headache is classified as mild migraine, moderate migraine, and severe migraine. This
classification is based on the duration and the intense of the attack. The treatment of this headache
disorder is produced based upon such classification. Mild migraine lasts for four to eight hours, it starts
with mild- moderate throbbing headaches, usually unilateral occur, and it happens infrequently
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(less than once each month), with common nausea.3,4 The patient might feel weakened to some degrees,
but still can manage the normal daily activities. Moderate migraine occur frequently (more than once a
month) and lasts for 4 to 24 hours. The pain is unilateral associated with common nausea and vomiting
may occur occasionally. The throbbing moderate headache might rise to severe headache and in this case
impair the patient. Severe migraine is a throbbing headache, unilateral pain that last for more than12 hours
and occur more than three times a month. This type of headache is also associated with nausea and
infrequent vomiting. Patients with severe migraine are always prevented from continuing their normal
daily activities and confine to bed.3,4
2.5 Migraine triggers
As mentioned before, migraine triggers are any factors that on exposure lead to the development of an
acute migraine headache.73 About 80% of migraine patients are able to identify at least one migraine
trigger. However, it varies from one individual to another as well as with age.1 Migraine triggers could be
endogenous (behavioral and biologic triggers) or exogenous (environmental, chemical, dietary and
infectious triggers), examples of each group are given below:73,1,75,76
- Behavioral:
- Environmental:
- Infectious:
- Dietary:
- Chemical:
- Hormonal:
Fasting, skipping meals, emotions sleep disturbances, stress, and exercise.
Bright light/ visual stimuli, odors, weather changes, cigarette smoke.
Upper respiratory infections.
Caffeinated beverages, Alcoholic beverages, aged cheeses, chocolate, ice cream.
Monosodium glutamate (MSG), tyramine, nitrates, aspartame.
Menstruation.
The effect or pathophysiology of these triggers could be explained based on different mechanisms.
However, trigger factors such as stress, sleep disturbances, fasting, skipping meals, menstruation, wine,
caffeine, tyramine, chocolate, and weather changes share the same mechanism of action, which involves
serotoninergic or noradergic neurons within brainstem modulatory pathway. Other trigger factors seem to
share the NO pathways, such as wine, nitrates, histamine, smoking, and MSG. Nevertheless, men should
keep in mind the possibility of the influence of more than one trigger to induce headache simultaneously.
Furthermore, when trigger affects the CNS directly, it means that it should be able to cross through the
blood- brain barrier.73 Most foods and beverages can not cross through the blood- brain barrier such as
histamine and tyramine, which means they might act peripherally at the level of the dural blood vessel or
the peripheral trigeminal nerve. In contrast, caffeine and phenylethylamine (chocolate) are amines that
cross the blood- brain barrier and modulate the migraine headache via LC or DR pathways (see page
29).73 Tyramine is biogenic amine that is found in wine (red – white), beer, cheese, smoked or pickled
fish, and yeast extract.73 Both phenylethylamine and tyramine are metabolized by MAO in the brain and in
the gut/ liver respectively.73,78 A well known example is the crises of “cheese effect”; sever headaches
associated with eating cheese and receiving MAO inhibitors.73 Studies show that there is no evidence that
patients classified within this subgroup of phenylethylamine and tyramine trigger factors have a deficiency
of the monoamine metabolizing enzyme, MAO. However, they indicate that dietary migraine patients
have a relative deficiency of the enzyme, phenolsulphotransferase P, compared with non- dietary
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migraine patients or controls. Phenolsulphotransferase is particularly active in the intestine where it
probably serves to detoxify phenols by adding to them a sulphate group. Part of this enzyme acts on
monoamine phenols such as noradrenaline and tyramine which called M, while the second part is known
as P. In somehow the M form of the enzyme seems to be reduced in dietary migraine less significantly
than the P form. No endogenous substrate for the P enzyme has yet been identified but it acts on phenol
itself and presumably also on a range of unknown phenols in chocolate, cheese and citrus fruit, which are
important "triggers" for dietary migraine.78 Both tyramine and phenylethylamine are believed to induce
the release of norepinephrine and its agonist affect on α- adrenergic receptors. This theory was also
supported by the observation that indoramin, a selective α- adrenergic blocking agent, seems to reduce the
development of headaches induced by tyramine or phenylethylamine.73 Remarkably, certain trigger might
not induce a migraine in every person, e.g in chocolate there are two ingredients that can trigger migraine
headaches, namely caffeine and phenylethylamine.75 These substances can constrict blood vessels
resulting in headache. Some people get headache if they eat chocolate but not when they drink caffeinated
beverages. That can be explained that some people may be sensitive only to phenylethylamine, while
others are sensitive only to caffeine. Moreover, in a single migraine sufferer, a trigger may not cause a
migraine every time.75
After all, all “migraine triggers” theories are based on clinical, and/ or randomized controlled studies in
which the strength of evidence are varied in each study. This brings some scientists to conclude that
triggers do not ‘cause’ migraine. Instead, they are thought to activate processes that cause migraine in
people who are prone to the condition.75,73 Moreover, these triggers might be symptoms of the migraine
prodrome such as the high tendency of migraineurs to eat chocolate before the migraine attack.73,5 In
conclusion, the effect of migraine triggers is kept as rational approach in the treatment strategy of
migraine patients by keeping an accurate headache calendar that reflects possible triggers in order to
manage it.1
2.6 Migraine theories
Migraine has been always identified as a cerebral cortexiii vascular disorder. Although, the reason behind
this disorder is still unknown, there are many theories explaining this chronic pain, such as vascular
theory, neurogenic theory, spreading depression of cortical activity theory, the theory of serotonin
abnormality, and lately, the theory of the ion channels abnormality.3 However, some scientists believe that
migraine results can be explained by a combination of vascular theory and neurogenic theory or by the
three theories together (vascular, neurogenic, and serotonin abnormality), also called the unify theory.
iii
The cerebral cortex is the largest part of the brain, it consists of four parts namely, the frontal lobe, temporal lobe, parietal
lobe, and occipital lobe. They all work together and individually and responsible for thinking, decisions, memory and emotions,
and creativity.72
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2.6.1 Vascular theory:
The old vascular theory was postulated and developed in the 1940s and 1950s.4,3 Based on the theory of
Wolff 4, abnormalities of blood flow appear to play a pivotal role in the etiology of migraine. According to
this theory, migraine is a vasospastic disorder results from intracranial (cerebral) vasoconstriction with
subsequent dilation of blood vessels, which activates pain fibers around the involved vessels.1,3,4,9,64
According to this theory, the migraine attack consists of two phases, the initial phase which starts with
cerebral vasoconstriction resulting in reduction of the oxygen transmission in the brain. At this stage, face
impairments, nausea, and vomiting will occur. After that, those narrow vascular blood vessels start to
expand back again to their normal size. This results in a sudden severe throbbing headache, vomiting,
dizziness, etc.1,2,60 Despite the observations that support this theory such as mechanical distention of
cerebral arties does lead to pain, this theory is still not proven yet.60 Furthermore, this theory has also been
replaced by neurogenic theory, because scientist believe that the decrease in cerebral blood flow is not
sufficient enough to produce the neurological symptoms, nor edema or focal tenderness associated with
migraines.3,1
2.6.2 Neurogenic theory:
This theory suggests also that migraines result from a reaction between the nerves and arteries that control
the face, eyes, nose, mouth, and jaws (the trigeminovascular system).9 It explains the premonitory
symptoms of the prodrome, which are difficult to explain by the vascular theory.64 It indicates that the
vasodilation is not the initial cause of the pain in migraine. An external (stress and hunger) or internal
stimulus results in central changes within the CNS and the subsequent neurogenic inflammation, which
leads to the vascular changes and subsequently to migraine headache.1,64 The pain will increase when the
protective covering around the brain and spinal cord becomes inflamed due to expansion or contraction of
arteries.9 One of the challenges to this theory was that stress may participate in migraine, but the actual
occurrence of the headache pain normally arises after, rather than during the stressful circumstance.64
2.6.3 Spreading depression theory:
Spreading depression, which is also known as “spreading depression of Leao”3,4 is a phenomenon
observed in mammals (non- human), which occurs in the cortex in response to a noxious (painful)
stimulus.3,4 In this phenomenon, a focal reduction in electrical activity of K+ to the cortex will occur
leading to an advancing wave of profound neural inhibition and distortion of the ionic balance with an
extremely high extracellular K+ concentration, and thus reduction of the blood flow in the brain (oligemia
of the cerebral cortex).13,73 This neural inhibition spread across the hemisphere at a rate of 2 to 3
milimeters per minute.13,4,3, Further, the EEGiv returns to normal within approximately 10 minutes.3,4
Similar symptoms were also found by Olesen in 1982 in patients with classic migraine. He indicated that
iv
An electroencephalogram (EEG) is a test to detect abnormalities in the electrical activity of the brain.
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during the attack a gradual spread of reduced blood flow (oligemia) was observed.3,4 This oligemia starts
in the occipital lob and advances interiorly. According to Olesen, oligemia is the main reason behind aura
in the classic migraine, and migraine may results from a developing process in the cerebral cortex that
may occur due to decrease in the cortical function, or decrease in the cortical metabolism, or due to
constriction of the cortical arterioles.10,3,4 His final conclusion was that the two forms of migraine are
different with respect to cerebral blood flow abnormalities and that they should be studied separately in
the future.10 Until then, this theory was criticized because it could not explain the activation or
sensitization of trigeminal afferents. Now it is postulated that the release of ions, arachidonic acids,
calcitonin gene- related peptide, or nitric oxide during spreading depression could either sensitize the
trigeminal nerve to pain directly or lead to vasodilation of dural blood vessels, and this in turn activates
the trigeminal nerve.14,15,73 On the other hand, this theory has been challenged because the regional
oligemia was only observed in patients with classic migraine (with aura).10 Consequently, it is believed
that the aura is associated with spreading depression, but not necessary step in the pathogenesis of the
migraine attack.14,15
2.6.4 The serotonin dysfunction theory:
This theory is also known as the “central theory “or the “biochemical theory”. This theory suggests that
low magnesium levels in the body may result in abnormal electrical activity and disturbance of some
hormones / neurotransmitters in the brain such as serotonin (5- HT).9 Throughout the years, there has been
no evidence that magnesium levels were the main trigger to migraine. However, this theory is more
acceptable than the pervious ones, since 5- HT is implicated in the etiology of migraine headache. 9,4
Raskin and Fozard 9,4 discovered that plasma and platelet 5- HT levels were varied during different phases
of migraine attack. Moreover, they indicated that larger amounts of 5- HT were excreted in urine during
most migraines. For more details see chapter (3 and 4).
2.6.5 Unify theory:
As mentioned before, this theory explains the migraine attack based on a combination of three previous
theories, i.e. vascular theory, neurogenic theory, and the central theory. It suggests that migraines begin as
a disturbance in the electrical activity in the brain, and this leads to changes in the brain stem and the
trigeminovascular system. There is no prove for this theory yet.9
2.6.6 The neurovascular disorder theory:
Recently, this theory starts to be very interesting one. It suggests that a genetic mutation in the voltagegated calcium channels leads to migraine headache. It is also known as the “channelopathy”. However,
this theory is still under investigation and no treatments based on this theory, are applied until now (see
chapter 5).
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2.6.7 Other hypotheses:
After all, many other theories were proposed including the effect of glutamate, nitric oxide, or dopamine
in migraine headache disorder. Yet none of them is scientifically proven.
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Chapter 3: Serotonin
3.1
Serotonin
3.2
The biosynthesis, release, regulation, and degradation of 5-HT in the body
3.3
Classification of serotonin receptors
3.3.1
5-HT1 receptors
3.3.2
5-HT2 receptors
3.3.3
5-HT3 receptors
3.3.4
5-HT4 receptors
3.3.5
5-HT5 receptors
3.3.6
5-HT6 and 5-HT7 receptors
3.4
The role of serotonin (receptors) in migraine
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3.1 Serotonin
The presence of a vasoconstrictor substance in the serum of clotted blood
NH2
was suspected for 130 years ago.15 In 1948, Page and coworkers were the
HO
first who could isolate an unknown vasoconstrictor substance “serotonin,
sero = serum and tonin = vasoconstriction” from the blood and indicate its
N
H
presence originally in the platelets15,27,50. Three years later, the chemical
structure of serotonin was identified as 5- hydroxytryptamine (5-HT)
(figure 10).27 Later on, it was discovered that serotonin was widely Fig. 10 The chemical
structure of serotonin.
distributed in animals and plants also in vertebrates, fruits, nuts and
venoms.27 In human, serotonin seems to be in its highest concentration in the wall of the intestine, 90% of
the total amount in the body is present in enteochromaffin cells. It is also present in the blood platelets in
high concentration. When tissues are damaged, aggregation of serotonin occurs in the damaged site. In
this case, serotonin will be accumulated in the platelets by an active transport system, and released to the
damaged site. In the nerve cells of the myeenteric plexus and the midbrain, 5-HT is acting as excitatory
neurotransmitter.15 It is noteworthy that smooth muscle in human body is slightly contracted by the effect
of 5-HT, while the effect of 5-HT in blood vessels is strongly dependent on the size of the vessel, the
species, and the prevailing sympathetic activity, e.g the constriction of large vessels such us arteries and
veins by 5-HT.15 According to R. F. Borne27,68 , 5- HT is probably the most chemical neurotransmitter that
is involved in the treatment of CNS disorders, including anxiety, depression, obsessive compulsive
disorder, schizophrenia, stroke, obesity, pain, hypertension, vascular disorders, migraine, and nausea. In
these treatments most of the used drugs are showing antagonizing effect on the serotonin actions. To
understand the role of serotonin in these disorders, it is important to understand the presynaptic regulation
of serotonin and the physiological role of various serotonin receptors.
3.2 The biosynthesis, release, regulation, and degradation of 5-HT in the body
Serotonin is synthesized in brain neurons and stored in vesicles, only a little is free in the cytoplasm under
normal circumstances.15 It is released through a nerve impulse into the synaptic cleft, and then interacts
with various postsynaptic receptors.27 5-HT is initially synthesized from tryptophan in a two- reaction
pathway. The synthesis of 5-HT is generated by the rate- limiting enzyme “tryptophan hydroxylase”
producing 5-hydroxytryptophan in neurons and in chromaffin cells, but not in platelets (figure 11).
Decarboxylation of the 5-hydroxytryptophan by amino acid decarboxylase will produce 5hydroxytryptamine (serotonin).15,27,51 Tryptophan hydroxylase (TPH) is strongly regulated by inhibitory
feedback via autoreceptors. When 5-HT neurotransmission is getting high, the presynaptic autoreceptors
are usually reacting to decrease 5-HT levels via G- protein signalling pathways (see pag. 4 and 5). It will
reduce the level of cAMP, and eventually the activity of protein kinase A and CaM kinase II. Because
phosphorylation increases the activity of TPH, the drop of kinase activity will reduce the synthesis of 5HT.17,51 On the other hand, short- term requirements for increases in serotonin synthesis appear to be
accomplished by a Ca+2- dependent phosphorylation of tryptophan hydroxylase, which changes its kinetic
properties without the synthesis of more enzyme.52
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COOH
COOH
Tryptophan hydroxylase
NH2
L- Aromatic acid decarboxylase
NH2
HO
NH2
HO
(= dopa decarboxylase)
N
H
N
H
N
H
Tryptophan
5-Hydroxytryptophan
5-Hydroxytryptamine
(serotonin)
O
HO
O
Monoamine oxidase
OH
Aldehyde dehydrogenase HO
H
N
H
N
H
5- Hydroxyindoleacetic acid (5-HIAA)
Fig. 11 The biosynthesis mechanism of serotonin and its metabolism.
Both newly synthesized and recycled 5-HT neurotransmitters are transported from the cytoplasm into
synaptic vesicles by the vesicular monoamine transporter (VMAT). VMAT is a non specific monoamine
transporter that is pumped into the vesicles via transmembrane proton- monoamine antiporter (figure 12).
Neurotransmission is initiated by an action potential in the presynaptic neuron, which eventually causes
synaptic vesicle to fuse with the plasma membrane in a Ca2+-dependent manner. Transporting it into the
nerve terminal require the transvesicular proton gradient as driving force.51,52 The proton- gradient is
controlled by a proton – ATPase pump that also resides in the vesicle membrane. 5-HT is stored as cotransmitter with diverse peptide hormones in neurons and chromaffin cells, such as somatostatin,
substance P or vasoactive intestinal polypeptide
(VIP).15
The actions of serotonin are terminated by three
major mechanisms when it returns to the cytoplasm;
diffusion, degradation by monoamine oxidase
(MAO), and uptake to the synaptic cleft through the
actions of VMAT.
Similarly to dopamine and L- Dopa degradation,
serotonin is broken down and hydrolyzed by MAO,
specifically type A. After that it will be
dehydrogenated with aldehyde dehydrogenase leading
to 5- Hydroxyindoleacetic acid (5-HIAA).15,51,52 5HIAA is easily excreted in the urine and is used as
indicator of the production of 5- HT in the body in
carcinoid syndrome.15 Degradation can also occur by
Catechol- O- methyltransferase (COMT) in the
extracellular space, however it has less effect in CPS
than CNS.51
5-HT can stimulate 5-HT1D
Fig. 12 The synaptic regulation of 5- HT
neurotransmitters
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autoreceptors to provide feedback inhibition.51 The selectively reuptake of 5-HT from the synaptic cleft
back into the presynaptic neuron occur by selective 5-HT transporter (5HTT), as well as by non selective
reuptake transporters such as norepinephrine transporter (NET) and dopamine transporter (DAT). The
regulation of these transporters is linked to the transmembrane of sodium gradient.51,15 Platelets and
neurons possess high affinity uptake mechanism of 5-HT, so that platelets become loaded with serotonin
as they pass through the intestinal circulation, where the local concentration of 5-HT is relatively high.15
There are some important regulatory differences between catecholaminergic and serotoninergic neurons.
Serotonin neurons are sensitive to changes in plasma levels of precursor amino acid tryptophan. This
means that dietary changes can regulate serotonin levels in brain. In addition, it appears that the increase
of the intracellular serotonin levels do not significantly alter synthesis in vivo, although in
catecholaminergic neurons, transmitter synthesis is influenced by end- product inhibition.52
3.3 Classification of serotonin receptors
As mentioned previously, 5-hydroxytryptamine (5-HT; serotonin) is a neurotransmitter essential for a
large number of physiological processes including the regulation of vascular and non-vascular smooth
muscle contraction, modulation of platelet aggregation, and the regulation of appetite, mood, anxiety,
wakefulness and perception.15,27,68 To mediate this astonishing array of functions, no fewer than 15
separate (sub) receptors have evolved, of which all but two (5-HT3A and 5-HT3B) are G-protein coupled
receptors.89 According to Hoyer et al,28 there are seven types of 5-HT receptors (5-HT1 to 5-HT7), each
one is located in a particular part in the body and has a specific pharmacological function to do. The
interesting receptors are 5-HT1, 5-HT2, 5-HT3, and 5-HT4.27 In 1994, the NC- IUPHAR has reclassified 5HT receptors and sub- receptors into 5-HT1 (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F), 5-HT2 (5-HT2A, 5HT2B, and 5-HT2C), 5-HT3, 5-HT4, recombinant (5-HT5A/5B, 5-HT6, 5-HT7) in addition to orphan
receptors.28 In this section, we will discuss the location and physiological function of each (sub-) receptor,
focusing on migraine related receptors, i.e. 5-HT1B, 5-HT1D, 5-HT1F, and lately 5-HT7 receptors, and then
summarize the given information over 5-HT receptors in table 3.1.
3.3.1) 5-HT1 receptors
In general, activation of 5-HT1 receptor is believed to be responsible for constriction of large intracranial
vessels (dilation), leading to headache. Many 5-HT1 receptor subtypes were discovered and even cloned in
the last century. Interestingly, it was discovered that the receptor gene in all 5-HT1 sub- receptors has no
introns and consists of seven transmembrane domains that are important for ligand binding and activation.
Moreover, all 5-HT1 sub- receptors share the presence of asparagines linked glycosylation sites and
putative phosphorylation sites for protein kinase.31, 36
The 5-HT1A receptor was first cloned in human (1988) and then in rat (1990). This receptor is mainly
expressed in the brain concerning the modulation of emotion.28 However, 5-HT1A was not detected in
blood vessels.30 The role of 5-HT1A receptor is effecting the neuronal inhibition and behavioral effects like
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sleep, feeding thermoregulation and anxiety through lowering the production of the second messenger
cAMP.27
On the other hand, the human 5-HT1B receptor was cloned in the early nineties in several laboratories, at
that stage it was called 5-HT1Dβ.35,36 This human receptor is localized on chromosome 6, region 6q13 and
consists of a 390 amino acid protein37. Cloning of rat, mouse and opossum 5-HT1B receptor showed a
missing of three amino acids in their receptor structure.38 These receptors are located not only in the CNS,
but also in the vascular smooth muscle of the rodent and human.27 5-HT1B receptor is considered as autoand heteroreceptor, when it is activated it inhibits the neurotransmitter noradrenaline release from the
sympathetic nerve terminals in the rat vena cava.39 An agonist to this receptor can inhibit the aggressive
behavior and food intake in rodent.27 The 5- HT1C receptor is recently renamed to 5-HT2C, based on
operational transductional and structural criteria.27,28
5-HT1D receptor was first identified in 1987 in bovine caudate40. Later on, during 1989- 1991, the first
cDNA sequence of 5-HT1D receptor was identified in canine thyroid cDNA library42, which was
characterized by ligand binding in transfected Cos-7 cells and LM (tK- cells).41 Scientists discovered that
the human and the dog 5-HT1D receptors have 377 amino acids. In human it is localized on the
chromosome 1, region 1p34.3- 36.3, while in dogs this receptor seems to lake to intron gene with a single
open reading frame (1131bp sequence).36,41,42 This sub- receptor is believed to affect the blood vessels in
the CNS, mainly at the cerebral cortex, which is related to migraine.27,15,55 It is also found that this
receptor mediate the smooth muscle contraction. 5-HT1D is also considered as terminal autoreceptor,
which is believed to affect the inhibition of neurotransmitter release by mediating a negative feedback
effect on transmitter release, and lowering the production of cAMP.15, 27 This in turn will inhibit the
activated trigeminal nerves and promote normalization of blood vessel and thus interrupt pain signal
transmission from the blood vessels to second order sensory neurons in the brain stem.55 (see 3.4)
In 1992, a clone (AC1) was isolated from human and 5-HT1E receptor was encoded. This receptor seems
to have 39% amino acid sequence resemble to 5-HT1A receptor and 47% to 5-HT1D receptor. The 5-HT1E
receptor has been reported to be expressed in human cortex, caudate, putamen, and amygdala, as well as in
dorsal root ganglia and in coronary artery. 43
5-HT1F receptor mRNA and the corresponding protein is preferentially expressed in the neuronal tissue
rather than vascular smooth muscle.30 The 5-HT1F receptor is expressed in various brain structures,
including cortex, hippocampus, trigeminal ganglia, and cerebral blood vessels.29 On the other hand, this
expression in peripheral tissues is limited to uterus, mesentery, and artery.29 Furthermore, it was reported
that this receptor show a higher amino acid homology with 5-HT1E (76%), than 5-HT1B (63%) or 5-HT1D
(60%) receptors.31 After cloning the human, rat and guinea pig 5-HT1F receptor, it became clear now that
5-HT1F gene encodes for a protein of 366 amino acids. 5-HT1F receptor seems to mediate inhibition of
dural plasma protein extravasation following trigeminal ganglion stimulation at the level of cranial
vasculature, through blocking the development of neurogenic inflammation.32,31
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3.3.2) 5-HT2 receptors
All 5-HT2 sub- receptors are positively coupled to phospholipase C, which after activation leads to the
conversion of PIP2 into IP3 and DAG. Subsequently, this will result in the release of Ca2+ from the
sarcoplasmatic reticulum and activation of protein kinase C. Type A is located in the CNS, PNS, smooth
muscles and platelets. It affects neuronal excitation, smooth muscle contraction, vaso- constriction and –
dilatation, besides its effect on sleep and feeding.28 Type B is present in several blood vessels, located on
the endothelium, while type C is not expressed in blood vessels.30 According to C. Ullmer,30 an activation
of the endothelial receptor will result in the release of NO, which plays a crucial role in vasorelaxant
activity through activation of soluble guanylate cyclase.
3.3.3) 5-HT3 receptors
5-HT3 sub- receptors are associated directly to membrane ion channels. This sub- receptor is apparently
involved in the depolarization of peripheral neurons, pain, and the emesis reflux.27,28, 15 It occurs in the
brain (area postrema) and is the main reason of vomiting reflex.27,15 The 5HT3 receptors affect the noneligand gated cation channels, which promotes entry of Na+ and Ca+ and hence neural depolarization.15
They cause excitation directly, even in the absence of any second messenger.15,27 Some of the medications
that are used in the treatment of migraine, anxiety, and cognitive and psychotic disorder are believed to act
at this site.27
3.3.4) 5-HT4 receptors
5-HT4 receptors are located in the CNS as well as in PNS, especially in the GI tract, bladder and heart,
but, they are absent in human ventricles.15 They are positively coupled to adenylate cyclase, which
enhance production of cAMP, leading to neuronal excitation and affecting the GI motility. Further, the 5HT4 receptor mRNA seems to be expressed in vascular endothelium, but no 5- HT4 receptor- mediated
endothelium- dependent vasorelaxations have yet been described.28
3.3.5) 5-HT5 receptors
5-HT5 receptors seem not to exist in blood vessels.30 However, after cloning of 5-HT5 receptors, they
were divided into two pharmacologically similar sub- receptors, namely 5-HT5A and 5-HT5B.33 The 5HT5A receptors are found in human, mouse, and rat, while 5-HT5B receptors were only expressed in mouse
and rat. In contrast to 5-HT5B receptors, 5-HT5A receptors distribution is not only limited to CNS, but they
are also distributed in neurons and neuronal- like cells of the carotid body. 5-HT5 receptors show some
pharmacological similarity with 5-HT1 and 5-HT7 receptors. However, the structural characteristics and
locations are not the same as 5-HT1 and 5-HT7.28 No functional correlation has been found for 5-HT5
receptors. The role of 5-HT5B is still unknown in vivo, whereas 5-HT5A receptors show a primary coupling
through Gi/ o to inhibit adenylyl cyclase activity and lower the production of cAMP.34
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3.3.6) 5-HT6 and 5-HT7 receptors
So far, little is known about the role of 5-HT6 receptor.15 In 2000, 5-HT7 receptor was fully
characterized.44 This receptor was identified in the rat and mouse brain cDNA library, the full length
sequence of the rat and mouse cDNA encodes a protein of 448 amino acids, showing less than 50%
homology with other 5-HT receptors.45 The molecular structure of human 5-HT7 receptor cDNA has an
open reading frame of 1335bp and encodes for a predicted protein of 445 amino acids. 46 In both human
and rat, the receptor gene has two introns interrupting the coding sequences; the first between TM3 and
TM4, while the second one is located near the end of C terminal region.47 The 5-HT7 receptor is expressed
in CNS and PNS of rat and human. This indicates that this receptor maybe involved in the regulation of
mood, learning, neuroendocrine, vegetative behaviors and circadian phase shifts.48 It is also believed to be
responsible for the regulation of vascular tone in a variety of blood vessels. 30 Apparently, there is no
inhibitory affect of 5-HT7 on adenylyl cyclase or any coupling of 5-HT7 to phospholipase C. In contrast,
this receptor seems to couple positively to adenylate cyclase via Gs proteins and enhance the production of
PKA.49 Moreover, it is obvious now that due to splice variation in 5-HT7 and 5-HT1A receptors, each one
is able to initiate a different transduction mechanism despite their molecular structure similarity. 30
Finally, all 5-HT receptors, their locations, and effects are summarized in table 3.1
Faculty of sciences Division of Medicinal Chemistry
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Table 3.1
Receptor
Location
Main effects
2nd messenger
1A
CNS
↓cAMP
1B
CNS
Vascular smooth muscle
↓cAMP
yes
1D
CNS
Blood vessels
↓cAMP
yes
1E
1F
Neural inhibition
Behavioral effects: sleep,
feeding, thermoregulation,
anxiety.
Presynaptic inhibition
Behavioral effects
Pulmonary vasoconstriction
Cerebral vasoconstriction
Behavioral effects:
locomotion
Not known
Neurogenic inflammation
Related to
migraine
no
CNS, PNS
CNS
PNS (uterus, mesentery,
artery)
Vascular smooth muscle
CNS
Neuronal excitation
PNS
Behavioral effects
Smooth muscle
Smooth muscle contraction
(gut, bronchi, etc.)
Vasoconstriction/
Platelets
vasodilation
Gastric fundus
contraction
CNS
Cerebrospinal fluid secretion
Choroids plexus
PNS
Neuronal excitation
CNS
(autonomic, nociceptive
neurons)
PNS
GI motility
CNS
Neural excitation
CNS
Not known
Neuronal- like cells of
the carotid body
CNS
Not known
CNS
Not known
CNS
Regulation of mood,
PNS
learning, vegetative
behaviors
Not known
↓cAMP
no
yes
↑IP3/ DAG
no
↑IP3/ DAG
↑IP3/ DAG
no
no
2A
2B
2C
3
4
5A
5B
6
7
Faculty of sciences Division of Medicinal Chemistry
Non- ligand gated no
cation channel
↑cAMP
no
↓cAMP
no
Not known
Not known
↑cAMP
no
no
yes
28
3. 4 The role of serotonin
(receptors) in migraine
As mentioned above, serotonin is
stored
and
released
from
aggregating platelets to affect local
vascular functions in different
ways. This monoamine is able to
cause contraction of blood vessels
by its direct action on smooth
muscle or by potentiating the effect
of other vasoconstrictor agents. It
can also induce vasodilatation by a
direct relaxing effect on smooth
muscle through inhibition of
adrenergic nerves, or by the release
of an uncharacterized relaxing
factor from endothelial cells.59 The
Cervicotrigeminovascular
hypothesis
linked
serotonin,
vascular, and musculoskeletal
changes to the development of
migraine headache.61,60 It suggests
that when enough trigger occur,
serotonin and norepinephrine are
released
from
brain
stem
specifically from the dorsal raphe
nucleus (DR), and locuse coeruleus
(LC), respectively. Consequently,
dilatation of the blood vessels will
occur in addition to vomiting
stimulations, and signals will be
sent along the nerve fibers to the
trigeminal nucleus (figure 13). It
also suggests that some of these
signals are returned from the
trigeminal nucleus to the dilated
vessels in a process called
antidromic
transmission
to
increase the dilatation or to cause
neurogenic
inflammation.
According to this hypothesis, the
symptoms of migraine
Fig. 13 The Cervico- trigemino- vascular hypothesis.
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(with aura) such as photophobia and nausea can be explained by the relation between the hypothalamusv
and the trigeminal nerve.55,60 It is believed that trigeminal nucleus is able to send signals centrally to the
hypothalamus resulting in photophobia and to the cervical muscles leading to muscle spasm and finally to
the thalamusvi to develop this signal to the cortical centers and transform it to pain. Important to note that
this relationship between serotonin, vascular blood vessels, trigeminal nucleus and migraine truly exist in
animal model but still unproven in human.60
A more specific hypothesis is the “Neurogenic dural inflammation theory”. It propose that migraine pain
is associated with inflammation and dilation of the meninges, particularly the dura vii. It suggests that an
increased 5-HT release from platelets or associated nerves might result in the release of NO from
endothelial cells or nerves in the area, which excites the trigeminal sensory nerves to release SP and
CGRP. This will result in neurogenic inflammation of the dura with plasma protein extravasation through
the endothelial gaps and consequently dilation of dural blood vessels and migraine headache (figure
14).65,66
v
The hypothalamus is lying just beneath the thalamus, it supplies input to areas in the medulla and spinal cord that control
activities such as heart rate, respiration, and fat metabolism. In reptiles, birds, and mammals, the hypothalamus regulates body
temperature. It also controls appetite and water balance and plays a part in emotional and sexual responses. The hypothalamus
is the bridge between the nervous and endocrine systems. It produces various hormones and regulates the pituitary gland. 74
vi
The thalamus in mammals receives all sensory messages from the spinal cord (except those from the olfactory receptors) prior
to being directed to the cerebrum's sensory areas. The function of the thalamus is to sort and interpret these messages before
relaying them to the appropriate neurons in the cerebrum. 74
vii
Dura is membrane (tissues) surrounding the brain and protecting it from external damage.
Faculty of sciences Division of Medicinal Chemistry
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Fig. 14 Neurogenic dural inflammation theory.
Dawn and Marcus60 suggest that serotonin may activate either presynaptic inhibitory or autoregulatory
receptors. They suggest that serotonin in the available serotonin pool might inhibit the firing of serotonin
containing dorsal raphe neurons, which in turn will inhibit serotonin from binding to the postsynaptic
membrane and thus inhibit pain signalling via the cervical muscles pathway and trigeminovascular
pathway. The role of serotonin in migraine is supported by the ability of serotonin- releasing agents to
induce migraine- like symptoms such as reserpine and fenfluramine. Additionally, most of migraine
patients have a positive family history of serotonin dysfunctions, in contrast to other types of headache e.g
cluster headache.67,60 More recently, the application of 5-HT1 receptors agonists to relieve the migraine
pain implicate that serotonin is the key molecule in migraine e.g. ergotamine (Cafergot) or sumatriptan
(Imitrex/ Imigrane).3, 64,60
In 1999, D. Chugani and her colleagues reported that some migraineurs women (without aura) have
serotonin level higher than the average level of serotonin synthesis throughout the brain. It appears also
that these women have a high level of serotonin even during headache- free intervals comparing to
migraine free women. They suggested that an excess of serotonin synthesis, may predispose the brain
decrease in blood flow in parts of the cerebral cortex and increase blood flow in the brain stem during
migraine attack. These changes might eventually lead to severe pain.58 Furthermore, they maintained this
proposition by indicating that migraineurs who are treated with beta- blockers had also increased serotonin
synthesis during the subsiding of migraine pain. They clarified that these beta- blocker help to ease
migraine by blocking 5-HT1A receptors leading to increase the breakdown of serotonin into component
molecules, than only the synthesis of serotonin (increase the rate of serotonin turnover).58
Alternatively, migraine has been regarded as “low- serotonin syndrome” based on different lines of
experimental evidence, including the reduction of urinary serotonin, elevation of its major metabolite 5HIAA during a migraine attack, the sudden and rapid drop of platelet serotonin in addition to the relief
effect of intravenouse injection of serotonin in lowering headache in migraineurs.15,3,60 Hargreaves and
Shepheard55 speculate that 5-HT1B and 5-HT7 receptors could be the link to the vasculature for the early
observations that suggested serotonergic activation as a key early process in the initiation of migraine
attack. Additionally, scientists believed that a significant proportion of migraineurs also suffer from
depression, which support the low- serotonin syndrome proposition too. In conclusion, it is hard to specify
the role of serotonin (receptors) in migraine attack, but it is definitely true that migraineurs suffer from
abnormal regulation of serotonin neurotransmitters.15,3 Internal factors may also play a crucial role in
serotonin irregularity such as estrogen withdrawal, reserpine agent, and m- chlorophenylpiperazine (mCPP), which decrease the peripheral serotonin pool and subsequently provoke the headache attack.62,63
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Chapter 4: Treatment of migraine
4.1
Prophylactic treatment of migraine headaches
4.1.1 Calcium- channel blockers
4.1.2 Tricyclic antidepressants
4.1.3 Beta- blockers
4.1.4 Serotonin antagonists
4.1.5 Anti- convulsants
4.2. Abortive treatment of migraine headaches
4.2.1 NSAIDs
4.2.2 Ergot and Ergot derivatives
4.2.3 The triptans
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Treatment of migraine
The treatment of migraine headache is a combination of non- pharmacological treatments such as
relaxation and lifestyle regulation, and pharmacological treatments such as anti- migraine medications.79
Based on the pathophysiology of migraine headache, many anti- migraine approaches were used. Most of
these anti- migraines act essentially on vascular targets.55 Accordingly, treatment of migraine is classified
as followed:1,4,55,79
-
Prophylactic treatment of migraine headaches.
Abortive treatment of migraine headaches.
The acute treatment attempts to relieve or stop the development of an attack, or the pain when the attack is
begun. The preventive therapy is applied even in the absence of the headache to reduce the frequency and
severity of expected attacks.4,79 In this chapter, we shall introduce these two kinds of treatment and their
suggested mechanisms briefly.
4.1 Prophylactic treatment of migraine headaches
Migraine prophylactic agents are believed to prevent occurrence of pain by inhibiting the central process
that is involved in the initiation of migraine attack or preventing the meningeal vasodilation.55 The dosage
of these drugs depends on the classification of migraine (sever-, moderated-, mild migraine). It should
start at low dose and increase slowly until therapeutic effects develop.79 Moreover, the effect of these
medications is estimated for 6- 12 weeks of use, and must not be used longer than 6 months. After that, the
medication should be discontinued and then reinstituted for another 6 month trail if headache frequency
and severity returned.4 Preventive treatment is suggested when 1) the patients’ daily routine is hindered
due to chronic migraine attack despite the abortive treatment, 2) non- effective or failure or troublesome
side- effects from acute medications, 3) overuses of acute medications, 4) in a special case, hemiplegic
migraine or attacks with risk of permanent neurological injury, 5) prevent “ the acute medication
dependency” by developing of rebound headache in case of very frequent headaches, 6) patient
preference, i.e. the desire to have as few acute attacks as possible. Prophylactic treatments are divided into
four major groups, namely:79, 55, 1
-
Calcium- channel blockers
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-
Tricyclic antidepressants
Beta- blockers
Serotonin antagonists
Anti- convulsants
It is obvious that all these prophylactic strategies are of little value once a migraine attack is progressed to
the point at which the trigeminovascular system become activated, which bring us back to the acute
treatment of migraine.
4.1.1
Calcium- channel blockers
Since 1981, clinical studies reported the influence of Ca+ channel
blockers in the treatment of migraine.4 Although, number of calcium
channel antagonists were synthesized and tested such as flunarizine,
diltiazem, verapamil, nifedipine, and nimodipine, none of these
agents has been approved by the FDA as anti- migraine.4,55
However, it was reported that verapamil (figure 15) has been
effective in acute treatments as migraine pain reliever. Verapamil is
administered as a racemic mixture of the R and S enantiomers.136
The exact mechanism of this treatment is poorly understood.
Furthermore, serious side effects were recorded by a chronic use of
flunarizine, such as depression, parkinsonismviii and extrapyramidal
symptoms (EPS)ix especially by the elderly, in addition to weakness,
headache, dry mouth, myalgia, and nausea. This medication seems
also to block H1- receptor which makes it less selective and thus
produce more undesired side effects.84
MeO
MeO
N
N
OMe
OMe
Verapamil (Racemic mixture)
F
N
F
N
Flunarizine
Fig. 15 The chemical structure of
some ion channel
antagonists.
4.1.2
Tricyclic antidepressants
Anti- depressants are divided into three groups, namely tricyclic anti- depressants (TCAs), monoamine reuptake inhibitors or selective serotonin re- uptake inhibitors (SSRIs), and monoamine oxidase inhibitors
(MAOIs). Only TCAs seems to be effective in the prophylactic treatment of migraine.79 TCAs are first
used in the 1950’s as anti- depressant drugs. Later on, TCAs were replaced with SSRIs and MAOIs
viii
Parkinsonism symptoms resemble to those affecting people with Parkinsson´s disease. The symptoms include tremors,
rigidity, temporary paralysis and extreme slowness of movement. These symptoms usually appears in the first few days and
weeks of medication administration.82
ix
EPS, is a neurological side effect of antipsychotic medication. EPS can occur within the first few days or weeks of treatment,
or it can appear after months and years of antipsychotic medication use. EPS can cause a variety of symptoms, e.g. involuntary
movements, tremors and rigidity, body restlessness, muscle contractions and changes in breathing and heart rate. 82
Faculty of sciences Division of Medicinal Chemistry
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because they showed fewer side effects and were less effective in case of a suicide attempt, compared to
TCAs.83
Another effective pharmaceutical use of Tricyclics is as analgesics for different types of pain, especially
neuropathic or neuralgic pain (like back pain in radiculitis) in addition to migraine prophylaxis. However,
these drugs failed in abortion of acute migraine attack. The mechanism of their anti-migraine action is
thought to be via indirect serotonergic route.83 The most commonly used TCAs for headache prophylaxis
are amitriptyline (Elavil®, Endep®, Tryptanol®), nortriptyline (Pamelor®), doxepin (Adapin®,
Sinequan®, and protriptyline (Vivactil®) (figure 16). 79,83 All six compounds share the same three fused
rings patron, i.e. two aromatic rings and one seven membered ring in between. The aromatic rings seem to
be essential for interaction (van der Waals) with the target receptors. The presence of azepane ring or
amine groups, which are mainly positively charged at physiological pH, will serve to increase ionic
interactions.
Amitriptyline is a potent blocker of the 5-HT receptors and other transporters. It is also an antagonist for
multiple neurotransmitter receptors, and a potent α1- receptor inhibitor which cause an anti- histaminergic
and anticholinergic effects.84 Although, its working mechanism is unknown and it is not FDA- approved
for treatment of migraine, it is wildly used especially for those with combination headaches. Recently,
scientists suggested that the effect of this anti- migraine is based on the inhibition of noradrenaline (NE) or
5-HT re- uptake or antagonize the 5- HT2 receptors in the cerebral vasculature and central neurons.84,85
For prophylaxis anti- migraine this medication is orally used starting with low dosage 10- 12.5 mg 1x per
night, and may gradually increase to 25- 150 1x per day.84,79 It is quickly absorbed and the bioavailability
is about 40%. The plasma concentration reach its maximum after 2- 12 hours. A lot of this medication is
metabolized into the pharmacological active form (nortriptyline), while the rest is excreted with the urine
as inactive form.84 The side effects of this medication are related to the anticholinergic properties of the
drug like dry mouth, dizziness, blurred vision, weight gain etc...4 Moreover, this medication might affect
patients to cardiac arrhythmias, and thus contraindicated in heart disease.
O
N
Amitriptyline
N
H
N
H
Nortriptyline
Protriptyline
N
Doxepin
N
N
Imipramine
N
N
H
Desipamine
Fig. 16 The chemical structure of TCAs.
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In addition to amitriptyline, imipramine and desipramine are used as migraine preventive drugs; however,
their use was based on anecdotal or uncontrolled reports.79 In 1987, the Raven Press had published that
long- term anti- depressant treatment of imipramine decreases the 5-HT2 receptor binding side, but does
not affect the 5-HT1 receptor binding. This decrease in 5-HT2 receptor binding sites seems to be blocked
when lesions of the noradrenaline system (NE) occur. However, the decrease in 5-HT2 receptor binding
sites does not correlate with a decrease in its function.79
4.1.3
Beta- blockers
Beta-blockers are used in the treatment of high blood pressure (hypertension). Some beta-blockers are also
used to relieve angina (chest pain) and in heart attack patients to help prevent additional heart attacks.
Beta-blockers are also used to correct irregular heartbeat, prevent migraine headaches, and treat tremors.88
One of the widely used anti– migraines are the adrenergic β- blockers such as propranolol (Inderal®),
metoprolol (Lopressor®, Toprol XL®), nadolol (Corgard®).1,4,79 Obviously, the structure of all βblockers consists of three main groups resembling the adrenaline chemical structure, which are the ether
hydroxyl tether, the amine group, and the aromatic moiety. The presence of the amino- and hydroxygroups are believed to increase the water solubility of the drug via H- bonds. Similar to adrenaline, the
amine group will interact with Asp113 of TM3, while the hydroxyl group and the aromatic rings seem to
interact with TM6 via Asn293 and Phe 290, respectively (figure 17).
TM6
Phe290
Asn 293
TM3
Ser204
TM5
Asp113
Ser208
Adrenaline
Propranolol
Acebutolol
Metoprolol
Oxprenolol
Asn312
Nadolol of sciences Division of Medicinal Chemistry
Faculty
36
TM7
Fig. 17 The chemical structures of adrenaline neurotransmitter and the adrenergic β- blockers.
Alprenolol
OH
HO
OH
O
H
N
O
HO
H
N
OH
O
O
H
N
N
H
OH
O
O
O
H
N
O
OH
HO
OH
H
N
O
H
N
OH
O
H
N
HO
The interaction of these β- blockers with TM5 seems to be very important for agonist activity compared to
adrenaline neurotransmitter. Replacing the catechol ring with a bulky substituent (e.g. propranolol) makes
it likely that the resulting compound will block adrenoceptors. Interestingly, all β- blockers appear to
interact with TM7 instead of TM5 via the ether tether.87 On the other hand, other β- blockers (partial
antagonists e.g. acebutolol, oxprenolol, and alprenolol) appear to show no effect in migraine therapy. This
supports the theory that these drugs do not act on the their β- adrenergic receptors in the treatment of
migraine.4 The action of migraine preventive drugs is uncertain, but it is believed to result from the
inhibition of β1- mediated mechanism. β- blockade results in inhibition of 5-HT release from the
monoaminergic nuclei (raphe nuclei) and of the NE from the locus coeruleus to prevent disturbances in
vascular control systems.55,79 In conclusion, only pure β- blockers (antagonists) will have a prophylactic
migraine effect such as propranolol, metoprolol, and Nadolol.4 The orally given doses of metoprolol for
example start with 100 mg 1x a day and can be gradually increased to 2x 100 mg a day. This medication is
quickly and totally absorbed after oral use, it goes through first pass- effect in liver. The bioavailability is
40- 50%, which increases by high doses. The maximum plasma concentration is reached after 1.5 hour. In
chronic use, the effect of this medication may last for four weeks.
According to the American journal of Cardiol, the treatment of migraineurs with β- blockers was about
60- 80% effective to produce > 50% reduction of the migraine attack.86,4 In general, all β- blockers share
Faculty of sciences Division of Medicinal Chemistry
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the same behavioral side effects, such as drowsiness, fatigue, lethargy. These medications are believed to
affect the CNS due to the reported side effects such as sleep disorders, nightmares, depression, memory
disturbance, and hallucinations.79 Importantly, β- adrenergic receptor antagonists are avoided in asthma,
advanced AV block (heart block), sinus bradycardia, and diabetes mellitus because of the interaction with
the used ion channels blockers such as verapamil and diltiazem.4,88
4.1.4
Serotonin antagonists
Prophylaxis migraine such as methysergide (Sansert®), methylergonovine (methergine®), cyproheptadine
(Periactin®), pizotifen (Pizo- A®), and mianserin (Mianeurin®) are all potent serotonergic antagonists.
They are effectively acting on 5-HT2A/B and 5-HT2C receptors. Methysergide and methylergonovine
belong to ergot alkaloids family, which will be discussed extensively in section (4.2.2). Cyproheptadine,
pizotifen, and mianserin contain a tricyclic system; two aromatic rings with 7- membered ring in between
that has different tethers (figure 18). Serotonin antagonists seem to have the same effect on the raphe
nuclei and locus coeruleus as that of the β- blockers.55,79
Cyproheptadine is not only an antagonist of the 5-HT2 receptor but also of histamine H1, and muscarinic
cholinergic receptors. It is available as 4 mg tablets, the total dose ranges from 12- 36 mg a day (2- 3 x a
day or at bedtime). Cyproheptadine is widely used in the treatment of children. However, it might inhibit
growth in children and reverse the effects of SSRIs. Its side effects are summarized with sedation, weight
gain, aching legs, nausea, light- headedness, and ankle oedema.79
N
S
H
N
N
Cyproheptadine
Pizotifen
N
Mianserin
Fig. 18 The chemical structures of tricyclic- serotonin antagonists.
4.1.5
Anti- convulsants
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Anti- convulsants (anti- epileptic drugs) have been heavily used offlabelx, usually for chronic pain. Recently, anti- convulsants were
suggested as prophylaxis migraine only when other drugs are not
effective. However, only some of these anti- convulsants were effective in
the treatment of migraine, namely sodium valproate (Epilim®, valpro®),
gabapentin (Neurontin®), and topiramate (Innofluor®, Topamax®),
(figure 19).1,79, 92 The precise mechanisms by which these medications
exert their anticonvulsant and migraine preventive affects are still
unknown. Although, preclinical (electrophysiological and biological)
studies suggest that the effectiveness of these medication is due to their
ability to block voltage-dependent sodium/ calcium channels or to enhance
the activity of the neurotransmitter GABA at some subtypes of the
GABAA receptor.90
H3C
ONa
H3C
O
Sodium valproate
H2N
COOH
Gabapentin
O
O
O
O
O
S
NH2
Sodium valproate is usually used in the preventive treatment of epilepsy.
O
At low concentrations, valproate increases potassium conductance,
O
O
resulting in neuronal hyperpolarization. As migraine prophylaxis, high
concentrations of this medication are required. Once valproate is
Topiramate
metabolized, it turns to its active form 2-en-valproic acid, which consists
of two chain fatty acid with 80% bioavailability.79 Due to its highly Fig. 19 The chemical structure
protein- bound, it accumulates in the brain. This enhances the activity
of anti- convulsants.
within central inhibitory pathways through inhibiting the degradation of
the neurotransmitter GABA and promoting its release via a blocking action at terminal ion channels. 55,79
Moreover, this medication seems to interact with the central 5-HT system and reduce the firing of 5-HT
neurons from the DR, which is responsible for pain in migraine attack.79 Studies showed that after 12
weeks of treatment with sodium valproate, between 44 to 50% of the patients achieved at least 50%
reduction in the frequency of migraine days or attacks compared with 14 to 21% on placebo.81When
sodium valproate is given as divalproex sodium (1:1 sodium valproate: valproic acid) the common side
effects such as mild stomach cramps, nausea, vomiting, weight gain, tiredness, weakness, and drowsiness
are less.93,79 Divalproex sodium is available in an enteric- coated form as 125, 250, and 500 mg. The
relative risk of hepatotoxicity from valproate in migraineurs is low compared to those with sever epileptic
drugs and mental retardation and organic brain disorder. Furthermore, this medication should not be given
in combination with analgesics that contain barbiturates due to its potential idiosyncratic interactions with
barbiturates, which might lead to severe sedation or even coma. It is also contraindicated for pregnancy
and a history of pancreatitis or a hepatic disorder such as chronic hepatitis or cirrhosis of liver.79
Noteworthy, topiramate has a totally different structure from valproate and gabapentin. It is a derivative of
naturally occurring monosacchride D- fructose with a sulfamate moiety.79 Although, the precise
mechanism of topiramate is unknown, preclinical (electrophysiological and biological) studies suggest
x
A drug is used off-label when the doctor prescribes that drug for a medical use other than the one that received Food and Drug
Administration (FDA) approval. Off-label prescribing is a commonly used and accepted medical practice. These drugs do
have FDA approval – but for a different use, such as the frequently prescribing of FDA-approved anticonvulsant medications as
a mood stabilizer instead of using it for chronic pain.137
Faculty of sciences Division of Medicinal Chemistry
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two other theories i.e. antagonizing the AMPA/ kainate subtype of the glutamate receptor, and inhibiting
the carbonic anhydrase enzyme CA, particularly isozymes CA II and CA IV.92,79 In contrast to other anticonvulsants, topiramate is related with loss of weight, which recommends patients to discontinue its use.79
4.2. Abortive treatment of migraine headaches
In these treatments, the drugs action is based on the inhibition of headache developing pathways. Based on
the previously mentioned mechanism (see page 12), acute anti- migraines are effective to stop one of three
pain pathways after the initial CNS dysfunction. The first pathway is hindered by inhibiting the
transmission of the pain impulses to the caudal brain stem nuclei, while the second pathway is by
inhibiting the release of vasoactive neuropeptides such as SP, CGRP, and NK1, which inhibits the vicious
cycle and the progress of headache pain, and finally, the third pathway is by inhibiting the trigeminal
sensitization process. The main classes of acute anti- migraine agents that are usually used as pain reliever
are:
- NSAIDs
- Ergot and Ergot derivatives
- Triptans
The maximum use of acute treatment should be 2-3 days a week.
Further, it is important to keep in mind that these medications have little
or no therapeutic value as prophylactic on the trigeminovascular system
until headache pain has started. In this section, we will explain in more
details the Ergot and Ergot derivatives and the Triptans as the mostly
related anti- migraines to serotonin disorder.
OH
Paracetamol
AspirinO
HO
O
O
4.2.1
NH
NSAIDs
Ibuprofen
Since years, aspirin, ibuprofen, sodium naproxen, fenoprofen,
ketoprofen, tolfenamic acid, and paracetamol were all known as nonsteroidal anti- inflammatory drugs, they all called cyclooxygenase
(COX) inhibitors.94 COX is an enzyme whose full name is
cyclooxygenase. There are three forms of the enzyme, COX-1, COX-2
and COX-3. COX-1 is largely responsible for protecting the lining of the
stomach, while COX-2 is involved in triggering pain and
inflammation.96 COX-3 is involved in the synthesis of prostaglandins
and plays a role in pain and fever. However, unlike COX-1 and COX-2,
COX-3 appears to have no role in inflammation.134 Due to their wide
distribution in different tissues, the inhibition of COX might be nonselective and harmful in some cases, e.g. the antiplatelet medication
which is used to avoid thromboembolic disorders, might cause stomach
bleeding. Classification of NSAIDs is not base on the chemical
O
OH
H
Fenoprofen
O
O
OH
H
O
Ketoprofen
O
OH
H
O
40
Faculty of sciences Division of Medicinal Chemistry
Naproxen sodium salt
O
ONa
Fig. 20 The chemicalHstructure
of some NSAIDs.
O
structure, they are mainly classified by their preferential inhibition of COX-1 and COX-2 (figure 20). In
general, NSAIDs are administered by oral route, they have a good bioavailability and bind to plasma
proteins with 90% on average.95 One of the most commonly used NSAID in migraine is aspirin or
acetylsalicylic acid (ASA). Aspirin inhibits both COX1 and COX2 non- selectively and irreversibly by
donating its acetyl group to the serine residue of the cyclooxygenase protein and converting it to salicylic
acid.79,95 A daily low doses of aspirin can be useful to prevent blood clotting. Recently, it is discovered
that aspirin inhibits colic tumor development, while high doses (500 mg) of aspirin is used to prevent
migraine attack in addition to its relief effect.95 Earlier studies showed that aspirin (13.5 mg/ kg) and
propranolol (1.8 mg/ kg) seem to reduce the frequency, duration, and intensity of attacks to the same
extent.97 However, aspirin has much less side effects compared to propranolol. Noteworthy, ibuprofen is
used as racemic mixture because the human body can convert the inactive (R) form into the (S) form, so
eventually 100% of the ibuprofen taken becomes active.138 Furthermore, long term use of aspirin or
ibuprofen might lead to ulcer or stomach lesion. Interestingly, acetaminophen or paracetamol turns to have
no anti-inflammatory properties and hence does not cause gastric lesions. This property is explained by
the fact that acetaminophen preferentially inhibits COX-3 present in the central nervous system, where it
penetrates readily. Paracetamol is currently the most frequently used analgesic and antipyretic drug. 98
4.2.2
Ergot and Ergot derivatives
The series of the first class anti- migraine derivatives were discovered late in the 19th century as ergot
extract and used in Germany and USA. Ergot is the natural product of a fungus (Claviceps purpurea),
which grows upon rye and other grains in a purple, curved body called sclerotium.99,4 This sclerotium is
usually used as a major commercial source of ergot alkaloids.4 Ergot was first identified as a poison that
introduces gangrene with burning pain, convulsions, hallucinations, severe psychosis, and even death in
the middle ages as a disease called the Holy Fire or St. Anthony’s fire.xi During 1918- 1920, A. Stoll
isolated ergotamine (Novartis®) as pure ergot alkaloid, which was introduced by Sandoz under the trade
name Gynergen a year after and marketed as a safer and more reliable form of the medieval midwife's
nostrum.99,4,15 Ergot contains a lot of other neurotoxic and vasoconstrictive alkaloids, which could be
isolated and used to heal migraineurs without poisoning
O
OH
them.99 In the 1930s, ergot common nuclease was for
A)
B)
the first time identified and named lysergic acid (figure
21).100,15 Five years later, Sandoz chemists succeeded in
H
NH
N
synthesizing ergonovine, which is later on developed to
H
H
methylergonovine (methergine®), that is widely used to
control postpartum hemorrhage.100,4 Dihydroergotamine
HN
HN
(DHE) is another ergot alkaloid that was synthesized in
1943 and was highly effective in migraine. In the same
Fig. 21 The chemical structures of A)
St. Anthony’s fire being in honor of saint at whose shrine relief was said to be obtained.
This and
reliefB)which
follow the
lyserigic acid
Ergoline.
migration to the shrine of St. Anthony was probably true, for the sufferers received a diet free of contaminated grain during
their stay at the shrine.
xi
Faculty of sciences Division of Medicinal Chemistry
41
year, Hofmann tried to resynthesize lysergic acid diethylamide (LSD). This lead compound was earlier
synthesized and showed non- promising results for therapeutic treatments in animals. Hofmann had tested
LSD (0.25 mg) on himself, he discovered that LSD had the same effect as natural ergot and derived to be
a potent, risky, and unpredictable to a medical application.100 Interestingly, Sandoz chemists succeeded to
synthesize an important anti- migraine drug, namely methysergide (Sansert®), which is used as
prophylaxis migraine.4 All ergot alkaloids contain at least one amino acid group or its derivatives in
addition to a tetracyclic system except Ergoline (figure 21).139 Other ergot alkaloids contain either methyl
group or a hydroxymethyl group at the carbon atom that bearing the carboxylic group, which might
display relatively little biological activity such as ergotaminine.4 Ergot alkaloids are classified into two
groups according to their hydrolysis, namely amine alkaloids and their relatives including ergonovine and
its derivatives yield lysergic acid and amine, and amino acid alkaloids (ergopeptine), which are alkaloids
of higher molecular weight and contain lysergic acid, ammonia, pyruvic acid or a derivative thereof,
praline, and other amino acid such as phenylalanine, leucine, isoleucine, and valine (figure 22).4
A) Amine alkaloids
OH
O
H
N
O
N
H
OH
N
O
H
N
O
N
O
O
N
O
O
H
N
N
H
H
HN
H
HN
Ergotamine
Dihydroergotamine
B) Amino acid alkaloids
O
H
N
O
H
N
OH
Methysergide
H
N
N
H
HN
Methergine
O
N
OH
OH
N
H
N
O
N
H
N
H
HN
Ergonovine
HN
LSD
Fig. 22 The chemical structures of A) Amine alkaloids and B) Amino acid alkaloids.
The pharmacological effect of ergot derivatives essentially based on the similarity of the binding sites to
those of serotonin self (colored in blue in figures 21 and 22).100 From their chemical structures, it is
Faculty of sciences Division of Medicinal Chemistry
42
obvious that they all are good hydrophobic ligands, which can cross the blood- brain barrier easily.xii
However, it is discovered that these ligands are not working selectively, which limits their therapeutic
uses. They have a direct effect on other receptors in CNS emetic centers i.e. the dopamergic receptors,
adrenergic receptors and even other 5-TH sub- receptors. This leads to undesired side effects like nausea
and vomiting which are the same symptoms of a migraine attack.100,4,15 Further, there are four commonly
used anti- migraines among ergot alkaloids, namely methysergide, methergine, ergotamine, and
dihydroergotamine. Methysergide and methergine are classified as serotonergic antagonists, which are
usually used as migraine prophylaxis more than acute migraine drugs. Methysergide is an effective
preventive medication that is suitable in resistant headaches with high attack frequency in addition to
cluster headeache.79,15 Methysergide is a potent 5-HT2A/ C antagonist/ partial agonist, and 5-HT1B/ D
agonist, with a low affinity for 5-HT1 compared to 5-HT2 binding sites.15,79,102 It is believed that this
medication blocks the 5-HT2 receptor in the cerebral vessels and central neurons and this prevents the
release of SP, and CGRP.100 In combination with ergotamine, it helps synergistically to breakthrough
attacks, but due to their side effects, a (combined) methysergide should only reserved for sever cases in
which other migraine preventive drugs are not effective.79 In case of a combination of triptan and
methysergide, it is advised to wait at least for six hours after the use of triptan (24 hour for eletriptan,
fovariptan and naratriptan).84 Starting with a dose of (1 mg, 1x a day) before sleeping and could be
increased to (1- 2 mg, 2- 3x a day, max. 6 mg 1x a day) and should not be used longer than six months. To
avoid rebound- effect, the doses should be lowered in a trail of 2- 3 weeks gradually before discontinue
treatment.84 The bioavailability is 13% after a strong first pass- effectxiii. It is metabolized in liver to
methylergometrine and glucuronidemetabolieten. About 56% of this medication is excreted in the urine as
methylergometrine or methysergide.84 In addition to the common side effects of ergots, methysergide is
capable of causing retroperitoneal fibrosisxiv and fibrotic complications (scar tissue that forms on the heart
or lungs or in the gut)100,79,84. This medication is absolutely contraindicated in pregnancy, peripheral
vascular disorders, sever arterio sclerosis, coronary artery disease, severe hypertension, thrombophlebitis
or cellulites of the legs, peptic ulcer disease, liver or renal function impairment, valvular heart disease. 79
Moreover, methergine should be avoided for patient with high blood pressure or toxemia (poisons
circulating in blood) or stroke.
Ergotamine and DHE are both acting on 5-HT1 receptors selectively. Although they are classified as
antagonists, they show partial agonist activity in some tissue, which may account for their activity in
treating migraine as abortive treatment.15,4 DHE is also potent for a number of other biogenic amine
receptors, such as 5-HT2A/2B, D2 dopamine, α1- and α2- adrenergic receptors.4 Both ergotamine and DHE
are believed to block the release of two important vasoactive neuropeptides currently thought to be
involved in migraine, SP and CGRP.4,15,100 However, DHE seems to avoid much of the hypertensive and
xii
The ability of the drug to diffuse through the blood- brain barrier is varied from very hydrophobic drugs that fail to enter the
CNS because they remain adsorbed to the membrane, and less hydrophobic drugs that can cross the blood- brain barrier and
thus the CNS, and finally the relatively hydrophilic drugs that do not cross the blood- brain barrier unless applied at high
concentrations.101
xiii
The first pass effect is a phenomenon of drug metabolism. After a drug is swallowed, it absorbed by the digestive system and
enters the portal cicualtion, which is later on carried through the portal vein into the liver. 140
xiv
Retroperitoneal fibrosis is a disorder in which the tubes that carry urine from the kidneys to the bladder are blocked by a
fibrous mass in the back of the abdomen.
Faculty of sciences Division of Medicinal Chemistry
43
emetic effects of ergotamine and also appears to be free from risk of
drug related rebound headaches. Additionally, DHE is much less
vasoconstrictive than ergotamine, which brings some scientists to
argue that its antimigraine action may have some anti-inflammatory
effect on blood vessels.100 DHE is given as intramuscular injection (1
mg every 30- 60 min. as long as needed, max. 3 mg 1x attack, max. 6
mg a week), as well as nasal spray (0.5 mg in one doses for each nose
hole every 15 min. as long as needed, max. 2 mg 1x attack, max. 2 mg
per 24 hour, max. 8 mg a week). Ergotamine is given orally as well as
rectal in combination with coffeinexv (1- 2 mg 1x in the beginning of
the attack, max. 2x a week).84 The bioavailability varies per person and
attack (0- 2% after oral administration, and 1- 5% after rectal
administration via “first- pass” effect).84 Finally, ergotamine and DHE
are both absolutely contraindicated in pregnancy and during breast
feeding, because they transport to the baby with the milk leading to
vomiting, diarrhea, weak pulse, changes in blood pressure, or
convulsions (seizures) in nursing babies.100,4
4.2.3 The triptans
The triptans have been available since the early 1990’s, and in contrast
to the general belief, the first triptan (sumatriptan) was not developed
as an abortive anti- migraine medication, but as a pharmacological
tool. It was tested as agonist of the serotonin 1- like receptor (now
known as 5-H1B) on dog saphenous vein, and showed a contraction
effect on the vein. On the other hand, this triptan seemed to have a
relaxation effect on the cat saphenous vein because it acts on another
receptor, namely 5-HT7.103 In the 1950’s, Heyck had suggested that the
migraine headache is related to the vascular mechanism of the opening
of arteriovenous anastomosesxvi. He proposed that a stimulation of the
serotonin 1- like receptor in the cranial circulation redistributes carotid
blood flow, which is the same foundation in the use of ergot.104 This
suggestion lead to the introduction of using triptans in the abortive
treatment of migraine. Noteworthy, the drug action of triptans on
arteriovenous anastomoses is never been considered important in the
pathogenesis of the migraine headache. In the 1960’s Sicuteri had
suggested that triptans are structural analogues of serotonin (figure
23).105
The synthetic method of sumatriptan was initially focused on the
systematic modification of the 5-hydroxyl group of 5-HT in order to
Sumatriptan
Almotriptan
H
N
O O
N S
H
N
Eletriptan
H
N
O O
N S
N
Naratriptan
H
N
S
O O
Rizatriptan
N
H
N
H
N
S
O O Zolmitriptan
N
H
N
N
N
N
Frovatriptan
N
O
Fig.
23 The
chemical
structure
The caffeine present in many ergotamine-containing combinations helps ergotamine work
better
and faster
byHcausing
more
N
of
the
Triptans.
of it to be quickly absorbed into the body.
O
NH
xvi
Arteriovenous anastomoses is the vascular structures, which establish direct communications between arteries and veins. 108
xv
N
44
Faculty of sciences Division of Medicinal Chemistry
H
N
H2N
O
N
H
ascertain which properties of this group, if any, are important for activity and selectivity at the 5-HT1
receptor (scheme 1). These replacements of the hydroxyl group with a hydrogen atom and a selection of
functional groups gave compounds that were 5- 50 times weaker than 5-HT at the 5-HT1 receptor and nonselective with respect to the 5-HT2 receptor. However, their poor activity at 5-HT3 was a good result.121
5-Carboxamidotryptamine was found to be ca two-fold more potent as a 5-HT1 agonist and ca 25 times
less potent as a 5-HT2 agonist compared with 5-HT in-vitro. It showed a degree of potency and selectivity
at the 5-HT1 receptor, however when this lead compound was examined in-vivo, it caused actually a
vasodilatation of the carotid circulation in the dog, and led to a profound fall in blood pressure. This result
was eventually clarified that 5carboxamidotryptamine was a very
potent agonist at a poorly characterised
5-HT receptor that mediated vascular
Replace OH with
relaxation, namely 5-HT7 receptor subH, OMe, Cl, Me, H2N
type. This receptor was very similar to 5-Hydroxytryptamine
the
5-HT1
receptor
but
pharmacologically distinct, and thus
the designed compounds that were
selective for the 5-HT1 receptor, with
Substituted amides
respect to 5-HT2 and 5-HT3 receptors,
and also mediated vascular relaxation
via the 5-HT7 receptor would be
beneficial.121
Further, they discovered that 5carboxamidotryptamine was ca 20
NH2
NH2
times more potent than 5-HT at the 5HO
X
HT7 receptor relative to the 5-HT1
receptor.
In conclusion, 5N
N
carboxamidotryptamine as a lead
H
H
non- selective 5compound is similar to serotonin, but
HT1/ 5-HT2 , but
with a modification in the amide
Combining positive features
poor on 5-HT3
substituent in the five-position, the
NH2
NH2
activity on the 5-HT1 receptor is
O
O
gained and at the same time reduce or
Z
H2N
eliminate the activity at the other subtypes. Alkylation of the primary amide
N
N
H
H
function of 5-carboxamidotryptamine
5- Carboxyamidotryptamine
Z = Me2N or
with small alkyl groups gave
about 50x selective for 5Me2CHNH slightly
compounds with marginal selectivity
HT1but not selective between
selective for 5-HT1
5-HT1 and 5-HT7 receptor subover 5-HT7
for the 5-HT1 receptor. Finally, to
types
produce a series of amides that are all
selective for the 5-HT1 over the 5-HT7
receptor (by 20-100 fold), a
45
NH2
Faculty of sciences Division of Medicinal Chemistry
NH2
X
H
N
N
H
X =O
H N
H N
O
S
O
N
H
CH2 group between the amide and the indole ring was introduced. The same results were obtained by
introducing sulphonamide equivalent of 5-carboxamidotryptamine. By combining these features Nmethylcarboxamide, AH25086, was synthesized, which produced a pronounced vasoconstriction in the
carotid arterial bed in dog, and had minimal other effects.121
Triptans are migraine- specific abortive agents that are 5-HT1B/ 1D agonist, Hargreaves and Shepheard55
were able to indicate the location of
each receptor and the effect of the
triptans on them. They indicated that
there are three 5-HT1D receptors which
Sumatriptan
GR43175
are distributed in three different
locations in the human body, namely
the trigeminal inhibitory 5-HT1D
1. change to sulphoamide
2. Introduce steric hindrance on terminal NH2
receptors, the trigeminal ganglia
inhibitory 5-HT1D receptors, and nuclei
Scheme 1: The major steps in the discovery of sumatriptan.
tractus solitarii inhibitory 5-HT1D
receptors. Trigeminal inhibitory 5HT1D
receptors
are
located
prejunctionally on trigeminal nerves
projecting peripherally to dural
vasculature, where they modulate neurotransmitter release, inhibit activated trigeminal nerves, and
normalize blood vessel caliber. This lead to the belief that inhibitory 5-HT1D might terminate attacks
peripherally. The trigeminal ganglia inhibitory 5-HT1D receptor seemed to interfere with nociceptive
signals to brainstem second- order neurons initiated by peripheral blood vessel dilation, and possibly to
the neurogenic inflammation too, and sensitized sensory nerve endings. Finally, the nuclei tractus solitarii
5-HT1D receptors are believed to control the central nausea and vomiting.
Moreover, Hargreaves and Shepheard detected two kinds of 5-HT1B receptors, namely vasoconstrictor 5HT1B, and vasodilatory 5-HT1B. The vasoconstrictor 5-HT1B occurs on human meningeal blood vessel
smooth muscle and some of human coronary arteries, while the vasodilatory 5-HT1B occurs on human
vascular endothelium in meningeal and coronary arteries. Activation of vasoconstrictor 5-HT1B receptors
leads to parameningeal vasoconstriction, while the activation of the other one leads to vasodilation, which
might initiate migraine pain. Hargreaves and Shepheard55 mentioned that 5-HT7 receptors are also
involved in the initiation of migraine headache by initiating the meningeal vasodilatation which activates
the trigeminovascular system.
The presence of 5-HT1B and 5-HT7 vasodilating receptors could explain the “triptan- causing worsening
headache” or “recurrence of migraine”. When the 5-HT1B/1D agonist plasma concentration is fallen, the
smooth muscle vasoconstriction is reduced, while the endothelial vasodilation is maintained by the
endothelial 5-HT1B and 5-HT7 receptors leading to recurrence of migraine.55,106 Furthermore, the theory
that implicates anti- inflammatory effects of acute anti- migraine drugs is the main mechanism in
headache relief turns out to be not true. Through studies, it appears that medications that mediate 5-HT1D
receptor and inhibit neurogenic inflammation, but do not cause cranial vasoconstriction are ineffective in
Faculty of sciences Division of Medicinal Chemistry
46
the abortive treatment of migraine. This fact suggests that the vasoconstriction effect is the main reason
for migraine headache.107 Triptans have also an affinity to 5-HT1A and 5-HT1F receptors, but their relevant
clinical effect is still unknown.84
To date, there are six known/ synthesized triptans in addition to sumatriptan (Imitrex®, SUMA®, and
Imigrane®), namely Eletriptan (Relpex®), Zolmitriptan (Zomig®), Naratriptan (Amerge®), Almotriptan
(Axert®), Rizatriptan (Maxalt®), and Frovatriptan (Frova®).84 They are used as acute anti- migraines for
migraine with or without aura. Triptans (e.g. sumatriptan) have three potential action mechanisms; the
cranial vasoconstriction, the inhibition of trigeminal neural (breaking of the dilator cycle), and finally the
inhibition of neurons transmission via the trigeminocervical complex (figure 24).84,55 The vascular
mechanism (cranial vasoconstriction) occurs when 5-HT1B/ 1D agonist selectively limits pain- producing
intracranial extracerebral blood vessels by direct action at 5-HT1B receptor in the vascular smooth
muscle.114 While the neurogenic mechanism (inhibition of trigeminal neural) probably occurs at 5-HT1D
receptors by the inhibition of the peripheral trigeminal nerves, which prevents neuropeptides release from
the activated peripheral terminals and subsequently removes the influence of CGRP, SP.115 The central
mechanism (inhibition of neurons transmission) occurs probably at 5-HT1D receptors within brain stem
sensory trigeminal nuclei that interrupts pain transmission from cranial structure, which would otherwise
pass through these central pain relay stations (not shown in the figure below).116
Faculty of sciences Division of Medicinal Chemistry
47
Fig. 24 The acute anti- migraine action on the migraine attack pathway.
During 1999- 2002, extensive studies investigated the involvement of 5-HT1B, 5-HT1D, and additionally 5HT1F receptors in sumatriptan mediated vasocontractile response in human and some animals (pigs, rabbit,
dogs, and bovine) common carotid artery (CCA), cerebral arteries and carotid arteriovenous anastomoses
(AVAs). These studies established that the triptans mediating mechanism consist of the three previous
mentioned action mechanisms.117,118,119 However, they indicated that 5-HT1D and 5-HT1F receptors are not
involved in the mediating effect of sumatriptan. In these studies, a selective antagonist at the 5-HT1D
receptor (GR127935) was used, which inhibits the sumatriptan- induced carotid vasoconstriction in pigs,
and dogs. Unfortunately, this selective antagonist was not able to distinguish between these 5-HT1D and 5HT1B receptors. In this respect, two other potent compounds were tested, namely BRL15572 and
SB224289. These two potent compounds have shown a very high selectivity to human 5-HT1D and 5-HT1B
receptors, respectively.117 Table 1 shows the binding affinity (pKi values) of sumatriptan, SB24289,
BRL15572, and GR127935 at human cloned 5-HT1 receptor subtypes:117
Table 4.1
Sumatripran
GR127935
SB224289
BRL15572
5-HT1A
6.4
7.2
< 5.5
7.7
5-HT1B
7.8
9.0
8.2
6.1
5-HT1D
8.5
8.6
6.3
7.9
5-HT1E
5.8
5.4
< 5.0
5.2
5-HT1F
7.9
6.4
< 5.0
6.0
Moreover, the dose- related decreases in carotid arteriovenous anastomotic conductance by sumatriptan
(30, 100, and 300 μg kg-1) does not change in animals treated with 1 mg kg-1of BRL15572 (max. decrease:
72 +/- 5%), while it decreased to (30 +/- 11%) by 1 mg kg-1 of SB224289, and (3 +/- 7%) by 3 mg kg-1 of
SB224289. These results indicate that sumatriptan limits porcine carotid arteriovenous anastomoses
primarily via 5-HT1B, but not via 5-HT1D receptors.117 On the other hand, RT- PCR experiments on the
human and bovine cerebral arteries showed a strong signal for the 5-HT1B receptor, weak signal for 5HT1F receptor, and no signal for 5-HT1D receptor. These studies concluded that the triptan- induced
contraction in brain vessels is mediated exclusively by the 5-HT1B receptor, which is also present in a
majority of human coronary arteries. Furthermore, they suggested that selective 5-HT1D and 5-HT1F
receptor agonists might represent new anti- migraine drugs devoid of cerebro- and cardiovascular
effects.118 The insignificance or no involvement of 5-HT1D receptor in the vasocontractile response was
also indicated in another study in rabbit CCA.119 In this study, they indicate that sumatriptan- mediated
vasocontractile response was strongly antagonized by SB216641 and weakly antagonized by BRL15572
with its affinity for 5-HT1B subtype, but not for 5-HT1D subtype. Interestingly, they also studied the role
of signalling molecules such as G proteins, inositol phosphates and L- type voltage dependent calcium
channels in this response.119 From earlier experiments, it is obvious that both 5-HT1B and 5-HT1D
Faculty of sciences Division of Medicinal Chemistry
48
subtypes are coupling to Gi/Go proteins, and inhibit cAMP formation, stimulate phospholipase C (PLC),
increase inositol phosphates and intracellular calcium.120 The results indicate that CCA expresses 5-HT1B
receptor subtype and sumatriptan induces vasocontraction by stimulating these receptors, which is mainly
mediated by the activation of L- type voltage dependent calcium channels, but not by the PLC pathway,
and the vasocontraction is mediated by PTX sensitive Gi/ Go proteins.119
All triptans activate central and peripheral 5-HT1B/1D receptors selectively, but they differ significantly in
time to maximal plasma concentration, lipophilicity, half- life, bioavailability, formulations available, and
elimination routes or metabolism, for more details see table 2.108, 84 The drug- drug interactions are
predicted by metabolism, while the rest of these features determine the clinical roles for each triptan.
According to their potency, triptans were divided into two groups; Group 1 that contains the faster onset,
higher potency, higher recurrence triptans such as sumatriptan, zolmitriptan, and rizatriptan in addition to
two lower recurrence triptans, namely almotriptan and eletriptan, while Group 2 contains the slower onset,
lower potency, and probably lower recurrence triptan, namely naratriptan and frovatriptan. Noteworthy,
frovatriptan has also 5-HT7 receptor effect, but it may not be clinically relevant at the usual doses.108
However, Hargreaves and Shepheard55 suggested that an 5-HT7 antagonist might be a migraine
prophylactic agent.
Triptans are widely used to treat migraine but have been associated with stroke, myocardial infarction
(MI), and ischemic heart disease (IHD). Recent studies investigate the relationship between triptans and
these lethal diseases. In these studies, 13.664 of 63.575 migraineurs were prescribed a triptan. It appears
that there is no association between triptan prescription and stroke (hazard ratio [HR] = 1.13; 95% CI
[confidence interval] 0.78- 1.65), MI (HR = 0.93; 95% CI 0.60- 1.43), while migraineurs who are not
prescribed a triptan had an increased risk of stroke (HR = 1.51; 95% CI 1.26- 1.82) and IHD (HR = 1.35;
95% CI 1.18- 1.54).109 Further, there are no other life- threatening side effects reported. The common
known side effects concerning the CNS are numbness, drowsiness dizziness, feeling sleepy and fatigue,
which are at a slightly high frequency in the more lipophilic triptans of group 1.108,84 In rare cases, nausea,
dry mouth and vomiting are reported.84 Further, hypotension, bradycardy, tachycardy, palpitation, and
increase of blood pressure shortly after administration especially in the elderly.84 Triptans sensations are
also reported in some patients such as tightening of the throat and chest, paresthesias, and warmth. The
“triptans sensations” side effect was postulated to be caused by esophageal narrowing or by reduced
muscle oxygen stores.110 Furthermore, the warning of “serotonin syndrome”xvii in some triptan prescribing
information appears to be based on a handful of anecdotal reports. However, serotonin syndrome can
occur specifically when serotonin- active medications are mixed, the likelihood for this adverse event is
rare.111 As shown below in table 2, sumatriptan, zolmitriptan, and rizatriptan have a significant MAO
metabolism and should not be given in combination with MAO inhibitors, while this is not the case in
naratriptan, eletriptan, and frovatriptan. Notably, almotriptan has a partial interaction with MAO
inhibitors, but it shows a high degradation with renal and cytochrome P-450, and is not contraindicated
with MAO inhibitors.108
xvii
Serotonin syndrome believed to occur when a combination of triptans with SSRIs is used, it consists of a triad of altered
mental status, such as confusion; dysautonomia, such as diaphoresis, diarrhea, hypertension, and fever; and neuromuscular
changes such as myoclonus and tremor.108
Faculty of sciences Division of Medicinal Chemistry
49
Sumatriptan has been used for almost 15 years and its safety profile is excellent.109 This medication is
available as an injection, nasal spray, tablet and rectal. Both, the spray and injection have rapid onset and
avoid the GI tract. This should be taken into consideration when prescribed to patient with significant
nausea and vomiting.1 It is effective in about 70% of migraine attacks, however, its short duration of
action is a drawback.
A very interesting medication among the triptans is eletriptan, this medication, as also indicated in table 2,
is mainly degraded by cytochrome P- 450 3A4 system (CYP3A4), which means that the plasma level of
this medication will be raised by erythromycin and presumably other 3A4- degraded medication.108
Subsequently, co- administration of this medication with many usual 3A4- degraded medications
(competitive inhibitors) should be done cautiously, such as antiarrhythmics, antifungal agents, antibiotics,
calcium channel blockers, proton- pump inhibitors, SSRIs, leukotriene antagonists, and protease
inhibitors.xviii Additionally, eletriptan might show a P- glycoprotein pump effectxix because this medication
has a high lipophilicity and high oral bioavailability, which could be overcame by using high doses. This
means that, all medications that are acting on CYP3A4 and competitively inhibiting the P- glycoprotein
pump are raising the circulating concentrations of eletriptan in addition to its high dosage concentration to
avoid the P- glycoprotein pump effect. This causes peripheral unpleasant side effects when its plasma
levels are raised by competitive inhibition of its degradation by CYP3A4, which could affect the CNS if
the now inhibited pump does not actively eject the drug from the CNS. To conclude, co- administration of
this medication with selected P- glycoprotein pump inhibitors and substrates should be done with extra
care.112, 113
xviii
Antiarrhythiics: Amiodarone, quinine, Antifungal agents: Fluconazole, itraconazole, ketoconazole, miconazole, Antibiotics:
Clarithromycin, erythromycin, metronidazole, norfloxacin, toleandromycin, azithromycin, Calcim channel blockers:
Omeprazole, SSRIs: Fluoxetine, sertraline, fluvoxamine, Leukotriene antagonists: Zafirlukast, Protease inhibitions:
Amprenavir, indinavir,Miscellaneous agents: Grapefruit juice, nefazodone, cimetidine, cannabinoids. 108
xix
A P- glycoprotein pump has been described that actively ejects lipophilic medications from the CNS. 108
Faculty of sciences Division of Medicinal Chemistry
50
Table 4. 2 Triptans
Lipophilicity Tmax (h)
Halflife (h)
Low
2
Bioavailability Metabolism
Optimal doses
(mg), max./24h
Group 1
Sumatriptan
Tablet
Nasal spray
Subcutaneous
Rectal
1.5
60-90 min
25 min
1.5
Hepatic,
MAO- A,
renal
15
15
95
20
50,100,max.300
10,20, mx.20
6, max. 12
25, max. 50
Zolmitriptan
Oral
Moderate
1.5
2.5- 3
40
Hepatic,
CYP,
MAO-A
2.5, 5, max. 10
Rizatriptan
Oral
Moderate
1- 2
2- 3
40-50
MAO- A,
renal
10, 5, max. 2010
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Almotriptan
Oral
Moderate
1.4- 3.8
3.3- 3.7
70- 80
CYP3A4,
CYP2D6,
MAO- A,
flavinemonooxygenase,
renal
12.5, max. 25
Eletriptan
Oral
High
1.5- 2
3.6- 5.5
50
Hepatic,
CYP3A4
40, 80, max. 80
Naratriptan
Oral
High
2- 3
5- 6.3
70
Renal, CYP
2.5, max. 2.5
Frovatriptan
Oral
Low
2- 4
25
Renal,
hepatic
2.5, max. 5
Group 2
22- 30
Finally, this chapter will be ended with a summarized anti- migraines table, namely table 4.3:
Table 4.3. Prophylaxis and acute anti- migraine drugs
Drug
(Prophylaxis)
Group
Mode of action
Side effects
Pharmacokinetic
aspects
Notes
Flunarizine
Calcium
channel
blockers
Ca2+ antagonist, relax
blood vessels, increase
the supply of blood and
oxygen to the heart while
reducing its workload.
Depression,
parkinsonism,
EPS, nausea, dry
mouth, weakness
Used orally
Not approved by
the FDA as antimigraine
Also H1 receptor
antagonist
Amitriptyline
TCAs
5-HT receptor inhibitor
Also α1- receptor
inhibitor, antihistaminergic and anticholinergic effect
Faculty of sciences Division of Medicinal Chemistry
Dry mouth,
Used orally
dizziness, fuzzy
Quickly absorbed
vision, weight gain Bioavailability is
40%
Not approved by
the FDA as antimigraine
52
Metoprolol
β- blockers
Cyproheptadine 5-HT
antagonists
β- Adrenoceptor
antagonists
5-HT2 receptor antagonist
Also blocks histamine
H1-, muscarinic-,
cholinergic receptors, and
Ca2+ channels
Divalproex
sodium
AntiVoltage- dependent
convulsants sodium/ calcium channels
Fatigue, lethargy,
drowsiness
Sleep disorder,
nightmares,
depression,
memory
disturbance
Sedation, weight
gain, aching legs,
nausea
Used orally
Quickly absorbed
Bioavailability is
40%- 50%
Effective and
widely used for
migraine
Used orally
Rarely used
Tiredness, nausea, Used orally
stomach cramps,
vomiting, weight
gain
It has idiosyncratic
interactions with
barbiturates
Severe sedation,
coma
Drug
(Acute)
Group
Mode of action
Side effects
Pharmacokinetic
aspects
Aspirin
Ibuprofen
Naproxen
NSAIDs
COX- 1 and COX- 2
inhibitors
By long term use,
ulcer or stomach
lesion
Used orally
Paracetamol
Methysergide
Only used when
other drugs are not
effective
Notes
COX- 3 inhibitor
Ergot
derivatives
5-HT2A/ C antagonist/
partial agonist
Also 5-HT1B/ D agonist
Faculty of sciences Division of Medicinal Chemistry
Nausea, vomiting, Used orally
diarrhea
Rarely but
seriously,
retroperitoneal or
mediastinal
fibrosis
Effective but
rarely used, due
to side effects
and insidious
toxicity
53
Sumatriptan
Triptans
5-HT1B/ 1D agonist
Constrict large arteries,
inhibits trigeminal nerve
transmission
Used orally,
nasal spray,
subcutaneous,
rectal
Effective in about
70% of migraine
attacks, but short
duration of action
is a drawback
Chapter 5: Ion channels abnormalities related to
migraine
(Future treatments)
Faculty of sciences Division of Medicinal Chemistry
54
According to Hargeeaves and Shepheard,55 it is theoretically possible for all individuals to suffer a
migraine attack due to a “neurovascular disorder”. The frequency and occurrence of attacks in any
individual depends strongly on their CNS response to migraine specific triggers (see 2.4). This suggestion
is based on the theory that genetic abnormalities result in a lowered threshold of response to these specific
trigger factors in migraineurs resulting in a primary neural dysfunction within the CNS. In normal
individuals, who lack these genetic deficits, the presence of these trigger factors has no role in migraine
initiation because they would not breach the “migraine threshold”.124
Voltage- gated ion channels are heteromers containing protein subunits of about 30- 230 kDa, which form
the calcium- selective pores across the cell membrane. The voltage- gated calcium channels consist of six
functional subclasses, namely transient (T- type), long- lasting (L- type), neural (N- type), Purkinje cell/
granule cells (P/Q- type), and toxin resistant (R- type). They all belong to the category high- voltage
activated channels except T- type, which is activated by negative potentials and belongs to low- voltage
activated channels.24,79,128 Each subtype has different functions; T- type channels shape channels regulate
Ca2+ – dependent genes and enzymes, and N- type and P/ Q- type channels are involved in
neurotransmitter release. P- Type Ca2+ channels are widely distributed in cerebellar Purinje cells, and
mediate neurotransmitter release in the CNS and PNS, while Q- type Ca2+ channels are described in
Faculty of sciences Division of Medicinal Chemistry
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cerebellar granule cells.128
Since 1996, intensive studies were achieved to understand the relation between migraine and the
abnormalities in ion channels, especially in families suffering from familial hemiplegic migraine (FHM).
FHM is a rare autosomal dominant subtype of migraine with aura including hemiparesis and that at least
one first degree relative has identical attack.123 A minor head trauma is a recognized trigger of delayed
migraine aura, and can be associated with loss of consciousness, as in basilar migraine.122, 123 The early
studies of H. Wolff128 showed that some specific locations of the brain were relatively insensate when
acute pain is occurred, such as the stimulated intracranial extracerebral vasculature. Additionally, current
studies have shown that the brain of migraineurs has altered responsivity to transcranial magnetic
stimulations.125, 126 Interestingly, scientists have found that mutations in the CACNA1A gene are
associated with a wide spectrum of neurological phenotypes starting with mild episodic disorders, such as
migraine, FHM, episodic ataxia, to progressive cerebellar ataxia and severe cerebellar atrophy xx.122
According to R. Ophoff, FHM is a genetically simple disorder (autosomal dominant), it may occur due to
mutations in the CACNA1A gene via chromosome 19p13.69, 70,122 The CACNA1A gene encodes the α1A
subunit of a neural specific P/Q voltage dependent calcium channel that is primarily involved in mediating
the release of neurotransmitters, including monoamines and glutamate. This gives rise to amino acid
substitution in the pore- forming and voltage sensor regions of the α1a subunit of the channel. This leads to
a gain or loss of function of the calcium channel and consequently to electric instability of nerve cells and
thus calcium channels and brain dysfunctions.69,70,122 In 2001, a study on the relationship between delayed
cerebral edema and CACNA1A calcium channel associated to FHM was established. In this study it
appears that also another mutation in the CACNA1A calcium channels subunit gene, namely S218L is
involved in FHM and delayed fatal cerebral edema and coma after minor head trauma.122 The mutation
analysis of the CACNA1A gene using SSCP analysis on genomic DNA of families with extreme FHM,
and one subject was the asymptomatic daughter of a sporadic patient with hemiplegic migraine attacks,
showed that a new variant in exon 5 was found in both families. At the nucleotide position 928, a C was
changed to T, which replaces a hydrophilic serine for a hydrophobic leucine residue at codon 218
(S218L). This mutation is located in the small intracellular loop between the fourth and fifth
transmembrane parts of the first domain of the α1A subunit. Furthermore, there are at least five other
CACNA1A mutations that are related to coma during FHM attack, namely V714A, I1811L, T666M,
Y138C, and R583Q.122
Further investigations were done early this year to evaluate if the single- fiber electromyography
(SFEMG)xxi method can demonstrate a neuromuscular transmission deficit in migraine. In these
investigations they studied the mutations of CACNA1A gene on chromosome 19p13 in three groups
namely, migraineurs with aura excluding visual aura (MA) and with visual aura (VA), without aura
(MOA), and patients with episodic ataxia type 2.129 They indicated that neuromuscular transmission
impairment and the SFEMG abnormalities were limited to patients with migraine with aura (50% MA and
17% VA). This brings us back to the final conclusion of Olesen (spreading depression theory), that both
xx
Cerebellar ataxia is known as disorder of the nervous system which effects balance and coordination, while cerebellar
atrophy is a weakening or degradation of the cerebellum. 141
xxi
SFEMG is a selective EMG recording technique that allows identification of action potentials (APs) from individual muscle
fibers.132
Faculty of sciences Division of Medicinal Chemistry
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subtypes of migraine disorders (with and without aura) are distinct disorders.10 In this respect, the choice
of the treatment of migraine will be more specific and drugs that modified P/Q Ca2+ channels can be
useful in the treatment of migraine e.g. calcium channel blockade with verapamil is helpful in the
treatment of familial hemiplegic migraine as preventive anti- migraine.129,130 The treatment of FHM with
common anti- migraine abortive such as triptans and ergotamine are contraindicated, because of their
vasoconstrictive properties and concerns about stroke. An optional treatments are NSAIDs, antiemetics,
and narcotic analgesics.130 Currently, limited treatment can be offered to patients with calcium
channelopathies. Hopefully, analysis of the functional consequences of calcium channel mutations may
help to develop rational treatment for these diseases.
In contrast, common migraine is a genetically complex disorder (multifactorial polygenic) in which the
environmental factors increase genetic penetrance to produce the observed phenotype.70 It is believed that
genetic deficits cause a lowered threshold of response to a specific trigger factor in migraineurs more than
migraine- free individuals.55 Very recently, new studies investigated the role of potassium channel
encoding gene KCNN3 as a candidate of common migraine. KCNN3 is a neural small conductance
calcium- activated potassium channel gene that contains two polyglutamine tracts, encoded by
polymorphic CAG repeats in the gene. This gene plays a critical role in determining the firing outline of
neurons and acts to regulate intracellular calcium channels. These studies also investigated the molecular
genetic basis of migraine with and without aura. They analyzed the highly polymorphic repeat region
coding for a polyglutamine stretch, which constitutes part of the cytoplasmic tail of the channel protein.
They concluded that migraine patients have an excess of the allele coding for 15 poly- glutamines.133
Understanding the phenotypic expression of these monogenic disorders may shed light on the mechanism
and the treatments of prevalent and polygenic disorders such as migraine and epilepsy.
Chapter 6: Conclusions and Remarks
Migraine is a CNS disorder resulting from vasodilatation of the cranial/ cerebral brain vessels. The
pathophysiology of migraine attack is believed to be neurogenic inflammation. From the
pathophysiological evidence, the influence of the neurotransmitter serotonin (5-HT) and some of serotonin
receptors in the initiation of migraine headache was indicated. Drugs that stimulate 5-HT1 receptors and
lead to vasocontraction are beneficial in treating migraine. Although, it is still poorly understood why this
disorder occurs and who is exposed to it, all migraineurs agree that there is at least one trigger factor that
is responsible to initiate migraine attack; it could be e.g. environmental, behavioral, or chemical.
Triptan class of drugs, including sumatriptan, zolmitriptan, eletriptan, naratriptan, rizatriptan, almotriptan,
and frovatriptan are selective analgesic medications. They are believed to constrict the blood vessels by
affecting only in 5-HT1B/1D receptors, which makes it the best among the listed acute anti- migraines. All
triptans are 5-HT1B/1D agonists; they are very effective in relieving migraine headache. However, they do
not prevent or reduce the number of attacks of migraine. On the other hand, clinical usefulness of ergot
and ergot derivatives are limited because of their potentially serious fibrotic side effects and the restricted
Faculty of sciences Division of Medicinal Chemistry
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concomitant use of triptans. Other preventive migraines are non- selective or their drug action is unclear.
Based on genetic analysis, all migraineurs might share ion channel abnormality due to some specific gene
mutations, which is suggested to cause a neuronal hyperactivity, and thus CNS dysfunction. This
suggestion was finally supported by recent studies in which a mutation in the potassium channel gene
KCNN3 in migraine patients was found.
In final conclusion, further studies and genetic analysis are needed to understand the etiology of migraine
and to improve the treatment of migraine.
Acknowledgments
M. Duyvendakn is kindly acknowledged for her help in collecting references.
Dr. M. J. Smit is sincerely acknowledged for giving me the opportunity in reviewing my thesis and
supervising this thesis.
Professor G. J. Koomen is sincerely acknowledged for supervising this thesis.
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Faculty of sciences Division of Medicinal Chemistry
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