Download How? Morphine is a pain medication of the opiate type which is

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B = agonist
E = partial agonist
A = resting
C = antagonist
(background activity)
D = inverse agonist
Equilibrium between active and inactive forms
© Oxford University Press, 2013 1
N
N
HO
HO
How?
O
prodrug
HO
active
drug
Tramadol (prodrug), sold under the brandname
Ultram, is an opioid pain medication used to treat
moderate to moderately severe pain. When taken
as an immediate-release oral formulation, the
onset of pain relief usually occurs within about an
hour. It has two different mechanisms. First, it
works by binding to the µ-opioid receptor.
Second,, it inhibits the reuptake
p
of serotonin and
norepinephrine. It is often combined with
paracetamol (acetaminophen) as this is known to
improve the efficacy of tramadol in relieving pain.
H
N
O
HO
Mittens and Louise
Morphine is a pain medication of the opiate type
which is found naturally in a number of plants and
animals. It acts directly on the central nervous system
(CNS) to decrease the feeling of pain. It can be taken
for both acute pain and chronic pain.
HO
Morphine
Acetaminophen (Tylenol) foremost cause of acute liver
failure in the Western world
and accounts for most drug
overdoses in the United States
O
H
N
HO
CH3
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Opioid receptors are a group of inhibitory G protein-coupled
receptors with opioids as ligands. The endogenous opioids are
dynorphins, enkephalins, endorphins, endomorphins and
nociceptin. The opioid receptors are distributed widely in the
brain, and are also found in the spinal cord and digestive tract.
Brain opioid peptide systems are known to play an important role
in motivation, emotion, attachment behaviour, the response to
stress and pain, and the control of food intake.
The opioid receptor family originated from two duplication
events of a single ancestral opioid receptor early in vertebrate
evolution. Phylogenetic analysis demonstrates that the family of
opioid receptors was already present at the origin of jawed
vertebrates over 450 million years ago. In humans, this double
tetraploidization event resulted in the receptor genes being located
on chromosomes 1, 6, 8, and 20. Tetraploidization events often
result in the loss of one or more of the duplicated genes, but in this
case nearly all species retain all of the opioid receptors,
case,
receptors indicating
important and specific function. The receptor families delta,
kappa, and mu demonstrate 55–58% identity to one another,
and a 48–49% homology to the nociceptin receptor.
These are all
TM-7 G coupled
receptor proteins
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Dynorphin A is a form of dynorphin and an endogenous
opioid peptide with the amino acid sequence:
Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys.
H3C
N
O
CH3
O
cocaine
O
H
O
Dynorphin A contains a high proportion of basic amino acid residues, 29.4% basic residues, as
well as 41.2% hydrophobic residues. The dynorphins are found widely distributed in the CNS.
Their storage vesicles are larger and more dense and a stronger and prolonged stimulus is needed to
cause the large vesicles to release their contents into the synaptic cleft.
The dynorphins are found to be extraordinarily potent opioid peptides (called dynorphin (from the
Greek dynamis=power) to describe its potency.
Dynorphins exert their effects primarily through the -opioid receptors (KOR), a G-protein-coupled
receptor. Two subtypes of KORs have been identified: K1 and K2. Although KOR is the primary
receptor for all dynorphins, the peptides do have some affinity for the µ-opioid receptor (MOR), opioid receptor (DOR),and the N-methyl-D-aspartic acid (NMDA)-type glutamate receptor.
Dynorphins have been shown to be an important part of the process of cocaine addiction.
Although a single exposure to cocaine does not affect brain dynorphin levels, repeated exposures
© nigra
OxfordinUniversity
Press, 2013
to the drug increases dynorphin concentrations in the striatum and substantia
rats.
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An enkephalin is a pentapeptide involved in
regulating nociception (extreme pain sensations:
smashing your toe, cutting yourself, burning yourself,
etc.) in the body. The enkephalins are termed
endogenous ligands, as they are internally derived and
bind to the body's opioid receptors. Two forms of
enkephalin were discovered, one containing leucine
("leu"), and the other containing methionine ("met").
Both are products of the proenkephalin gene.
Met-enkephalin is Tyr-Gly-Gly-Phe-Met.
Leu-enkephalin has Tyr-Gly-Gly-Phe-Leu.
Morphine
Met-enkephalin
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α-endorphin
E d hi (contracted
Endorphins
(
d from
f
" d
"endogenous
morphine"are
hi " endogenous
d
opioid
i id
neuropeptides and peptide hormones in humans and other animals. They are produced by
the central nervous system and the pituitary gland. The term "endorphins" consists of two
parts: endo- and -orphin; these are short forms of the words endogenous and morphine,
intended to mean "a morphine-like substance originating from within the body". The
class of endorphin compounds includes -endorphin and several other related peptides.
The principal function of endorphins is to inhibit the transmission of pain signals; they
may also produce a feeling of euphoria very similar to that produced by other opioids.
 Endorphin is an endogenous opioid peptide with an amino acid sequence:
-Endorphin
Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr.
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Endomorphins are a group of endogenous opioid peptides consisting of
endomorphin-1
Tyr
Pro
Trp
Phe
NH3
endomorphin-2
Tyr
Gly
Phe
Phe
NH3
Endomorphins are tetrapeptides with the highest known affinity and selectivity for
the µ-opioid receptor. Endomorphin-1 may regulate sedative and arousal behaviors. It
is assumed that endomorphins are the cleavage products of a larger precursor, but
this polypeptide or protein has not yet been identified.
In rats similarly potent dosages of synthetic endomorphin and morphine produced
comparable amounts of pain relief. However, motor skills and breathing were
significantly impaired in those receiving morphine, while the endomorphin rats did not.
The morphine rats spent more time in the compartment where they had received
morphine, while the endomorphin rats did not. Only the morphine rats made efforts to
secure further doses of the drug. Endomorphin did not activate spinal glial cells, an
established morphine effect that helps to build tolerance of the drug.
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Nociceptin is a 17-amino acid neuropeptide, is the
endogenous ligand for the nociceptin receptor and acts on
numerous brain activities such as pain sensation and fear
learning. Nociceptin is the first example of reverse
pharmacology; the NOP receptor was discovered before
the endogenous ligand which was discovered by two
separate groups in 1995.
Nociceptin and its receptor are widely distributed
throughout the CNS.
Unlike morphine and other opioids that are used to
alleviate pain, nociceptin's role can counteract analgesia,
thus acting as an anti-opioid. Blocking the nociceptin
receptor can lead to an increased pain threshold and a
decreased tolerance development to analgesic opioids and
may help lower risks of addiction of many pain relievers
that are currently used.
Animals studies suggest that nociceptin plays plays a part
in both anxiety and depression. It appears that nociceptin
inhibits anxiety,
anxiety but also seems to perpetuate depression.
depression
Noiceptin been found to play both positive and negative roles in both learning and
memory. It is implicated in control of the cardiovascular system in blood pressure and
heart rate that vary by species. In the renal system, nociceptin plays a role in water
balance, electrolyte balance, and arterial blood pressure regulation.
In the gut, nociceptin has been found to have varying effects on the stomach and the
intestines. It also stimulates increased consumption of food. And finally, studies have
© Oxford University Press, 2013
shown that nociceptin may have an effect as an anti-epileptic drug component.
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The -opioid receptor (KOR) is a protein
that in humans is encoded by the OPRK1
gene. The KOR is one of four related
receptors that bind opioid-like compounds
in the brain and are responsible for mediating
the effects of these compounds. These effects
include altering nociception, consciousness,
motor control, and mood.
The KOR binds the opioid peptide dynorphin as the primary endogenous ligand. In addition
to dynorphin, a variety of natural alkaloids, terpenes and other synthetic ligands bind to the
receptor. The KOR may provide a natural addiction control mechanism, and therefore, drugs that
act as agonists and increase activation of this receptor may have therapeutic potential in the
treatment of addiction.
There is evidence that distribution and/or function of this receptor may differ between sexes.
KOR agonists are potent analgesics, and have been employed clinically in the treatment of
pain. However, KOR agonists also produce side effects such as dysphoria (profound state of
unease), hallucinations, and dissociation, which has limited their clinical usefulness.
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The µ-opioid receptors (MOR) are a class of opioid
receptors with a high affinity for enkephalins and betaendorphin. The prototypical µ-opioid receptor agonist is
morphine, the primary psychoactive alkaloid in opium.
Activation of the µ-opioid receptor by an agonist such as
morphine causes analgesia, sedation, slightly reduced
blood pressure, itching, nausea, euphoria, decreased
respiration, miosis (constricted pupils), and decreased
bowel motility often leading to constipation. Some of
these effects, such as analgesia, sedation, euphoria, itching
and decreased respiration, tend to lessen with continued
use as tolerance develops. Reduced bowel motility tend
to persist; little tolerance develops.
Opioid overdoses kill through apnea and fatal
hypoxia, often caused by combination with ethanol,
benzodiazepines, or barbiturates. Substantial tolerance
to respiratory depression develops quickly, and
tolerant individuals can withstand larger doses.
However tolerance to respiratory depression is lost
However,
just as quickly during withdrawal. Many overdoses
occur in people who misuse their medication after being
in withdrawal long enough to lose the tolerance to
respiratory depression. Less commonly, massive
overdoses have been known to cause circulatory collapse.
Opioid overdoses can be rapidly reversed through the
use of opioid antagonists, naloxone being the most
widely used example.
HO
naloxone
O
OH
N
© Oxford University Press, 2013 11
O
The -opioid receptor, also known as delta opioid
receptor or simply delta receptor, abbreviated DOR, is a
7-transmembrane G-protein coupled receptor, that has
enkephalins as its endogenous ligands. The regions of
the brain where the -opioid receptor is largely
expressed vary from species model to species model. In
humans, the -opioid receptor is most heavily expressed
in the basal ganglia and neocortical regions of the brain;
the basal ganglia, which is heavily GABA populated,
h been
has
b
li k d to major
linked
j depressive
d
i disorder,
di d suggesting
i
a possible role for the -opioid receptor in mood
modulation.
It is suggested that the pain modulated by the -opioid
receptor and that modulated by the -opioid receptor are
distinct types, with the assertion that DOR modulates the
nociception of chronic pain, while MOR modulates
acute pain.
A showing of selective delta opioid ligands.
Blue represents a common phenolic moiety,
yellow a basic nitrogen, and red a diethyl amide
moiety which isn't set in stone, but rather a bulky
region that fits into a hydrophobic pocket
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Addiction, dependence, sensitization and tolerance
• addiction – a brain disorder characterized by compulsive engagement in rewarding
stimuli despite adverse consequences
• addictive behavior – a behavior that is both rewarding and reinforcing
• addictive drug – a drug that is both rewarding and reinforcing
• sensitization – an amplified response to a stimulus resulting from repeated
exposure to it
• tolerance (desensitization) – the diminishing effect of a drug resulting from
p
administration at a ggiven dose,, higher
g
levels of a drugg are needed to gget
repeated
the same biological response, if a drug is withdrawn, distressing symptoms may
occur (dependency)
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Desensitization and Sensitization
Desensitization
• Receptors become desensititized on long term exposure to agonists
• Prolonged binding of agonist leads to phosphorylation of receptor
• Phosphorylated receptor changes shape and is inactivated
• Dephosphorylation occurs once agonist departs
1
H
Ion channel
O2C (closed)
O
Agonist
O2C
H
•Induced fit alters
protein shape
O
NH3
NH3
Agonist
+
+
Receptor
Receptor
•Opens ion channel
O2C
H
O
•Possibly phosphorylation
alters shape
•Ion channel closes
•Desensitization
Agonist
NH3
+
P
Receptor
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Desensitization and Sensitization
Sensitization
• Receptors become sensititized on long term exposure to antagonists
• Cell synthesizes more receptors to compensate for blocked receptors
• Cells become more sensitive to natural messenger
• Can
C result
lt iin tolerance
t l
and
d dependence
d
d
• Increased doses of antagonist may be required to achieve same effect (tolerance)
• Cells can become supersensitive to normal neurotransmitter
• Can cause withdrawal symptoms when an antagonist is withdrawn
• Can lead to dependence
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Electrical or chemical stimulation of the rat hippocampus causes strengthening
of synaptic signals, a process known as long-term potentiation (LTP), which is a
potential mechanism underlying memory and learning in the brain.
In "kindling", repeated stimulation of hippocampal or amygdaloid neurons
(from repeated withdrawal episodes) in the limbic system eventually leads to
seizures in laboratory animals. After sensitization, very little stimulation may be
required to produce seizures. Thus, kindling has been suggested as a model for
temporall lobe
l b epilepsy
il
i humans,
in
h
where
h stimulation
i l i off a repetitive
i i type
(flickering lights for instance) can cause epileptic seizures. Often, people
suffering from temporal lobe epilepsy report symptoms of negative effects such
as anxiety and depression that might result from limbic dysfunction.
The limbic system supports a variety of functions
including emotion, behavior, motivation, long-term
memory, and olfaction. Emotional life is largely
housed in the limbic system, and it has a great deal to
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do with the formation of©memories.
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Desensitization and Sensitization
Sensitization
Neurotransmitter
Normal response
Antagonist
No response
No response
Receptor
synthesis
Receptor
synthesis
Sensitization
Response
Increase
antagonist
Excess response
Stop
antagonist
No response
Tolerance
No response
© Oxford University Press, 2013 17
Dependence
Design of an antagonist for the estrogen receptor
Action of the estrogen receptor
Binding
site
AF-2
regions
H12
Coactivator
Coactivator
Estradiol
DNA
Estrogen
receptor
Dimerisation &
exposure of
AF-2 regions
CH3
Nuclear
transcription
factor
Transcription
OH
CH3
H
H
CH3
O
H
H
H
OH
How?
H
H
H
HO
Testosterone
Estradiol / Estrogen
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Design of an antagonist for the estrogen receptor
Binding interactions for estradiol
His 524
Me OH
H
H
Glu353
H
H
H
O
Hydrophic skeleton
H2O
Arg394
Estradiol
Note:
• Phenol and alcohol of estradiol are important binding groups
• Binding site is spacious and hydrophobic
• Phenol group of estradiol is positioned in narrow slot
• Orientates rest of molecule
© Oxford University Press, 2013 19
• Acts as agonist
Design of an antagonist for the estrogen receptor
Binding interactions for raloxifene
Asp351
N
H
Side
chain
His 524
O
Glu353
O
OH
H
O
S
Arg394
Raloxifene
Note:
Raloxifene is an antagonist (anticancer agent)
Phenol groups mimic phenol and alcohol of estradiol
Interaction with Asp-351 is important for antagonist activity
Side chain prevents receptor helix H12 folding over as lid
AF-2 binding region not revealed
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Co-activator cannot bind
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Design of an antagonist for the estrogen receptor
O
H
Tamoxifen - antagonist for estrogen receptor
H
H
H
H
H
O
N
O
Me
Estradiol
Me
O
H
H
in the body
T
Tamoxifen
if
(antagonist)
O
if metabolite
b li
Tamoxifen
(agonist)
Tamoxifen is currently used for the treatment of both early and advanced ER+
(estrogen receptor positive) breast cancer in pre- and post-menopausal women.
Additionally, it is the most common hormone treatment for male breast cancer. It is
also approved by the FDA for the prevention of breast cancer in women at high risk of
developing the disease. The use of tamoxifen is recommended for 10 years. A large
2006 STAR clinical study concluded that raloxifene is equally effective in reducing the
incidence of breast cancer, but after an average 4-year follow-up there were 36% fewer
uterine cancers and 29% fewer blood clots in women taking raloxifene than in women
© Oxford University Press, 2013 21
taking tamoxifen.
L = radiolabelled compound
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