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IL SISTEMA NEURONALE
GABA/GLUTAMMATO
Different Types of NTs
1.
Amine
a.
2.
Acetylcholine (Ach)
Monoamines
a.
b.
Catecholamines
i.
Dopamine
ii.
Norepinephrine
Indoleamines
i.
Serotonin
3. Amino acids
4.
a.
GUTAMMATO
b.
Aspartate
c.
GABA
d.
Glycine
Peptides
Amino Acid Neurotransmitters
• Inhibitory
– GABA and Glycine
– Hyperpolarize = don’t fire
• Excitatory
– Glutamate (Aspartate, Gly and DSer)
– Depolarize = fire
3
Deux types de neurones
Pyramidal cells
GLUTAMATE
Excitation
Interneurones
GABA
Inhibition
Glutamate Receptor Subtypes
COOH
H2N
Subunits
AMPA
GluR
1GluA1-4
4
COOH
GluN1
GluR
5-7, NR1,
GluK1-3
GluN2A-D
KA1,2
NR2A-2D
GluK4-5
GluN3A-B
Kainato
mGlu1
mGlu5
mGlu2
mGlu3
NMDA
mGlu4
mGlu6-8
Metabotropic receptors of glutamate
the family 3 of GPCRs
Ionotropic glutamate receptor subunit
4 subunits are necessary to make the channel
Ionotropic receptors of glutamate
Ionotropic receptors of glutamate
NMDA receptor
as a coincidence
detector :
requirement for
membrane
depolarization
10
Potential Gaba and Glutamate therapy
Physiological processes :
Memory
Learning
Orientation
Pathological processes :
Epilepsy
Ischemia
Alzheimer
Tranche d`Hippocampe
C
C
V
m
A
3
A
1
H
I
S
t
L
i
U
m
S
u
The only therapeutic application of glutamate neurotrasmitter
MEMANTINE
Brief Profile
Memantine – Innovation for Alzheimer Patients
Memantine is the first and only representative of a new class of Alzheimer drugs – a moderate affinity NMDA-receptor
antagonist.
Memantine has been developed by Merz Pharmaceuticals and is approved in Europe and the USA for the treatment of
moderate to severe Alzheimer's disease.
Efficacy of Memantine
Clinical data on memantine show
*
Benefit in cognitive and psychomotor functioning
*
Benefit in activities of daily living
*
Reduction of care dependence
*
Excellent tolerability|
H2N
Memantine
Memantine produces symptomatic improvements in learning under conditions of tonic NMDA receptor
activation in Alzheimer’s disease.
In contrast to first generation therapies, memantine is likely to show neuroprotective effects at
concentrations used in the treatment of Alzheimer’s disease and to slow down disease progression.
Physiological condition
NMDA receptors are transietly activated by mM concentrations of glutamate. In order to prevent
excessive influx, the ion channel is blocked by a Mg++ under resting conditions.
If the NMDA is activated by glutamate and the postsynaptic neuron is depolarized at the same time,
Mg++ leaves the ion channel and the Ca++ can flow in, which is important for learning processes.
Pathological condition
NMDA-protection with “Memantine”
GABA is a Gamma-aminobutyric acid
 Major inhibitory NT of the brain
 Usually involved with the transmission
from one part of the CNS to the another
 Most CNS neurons have GABA receptors
Neurotransmission by g-aminobutyric acid (GABA) is a major inhibitory
mechanism in the human central nervous system (CNS).
Postsynaptic GABAA ion channels open in response to the binding of GABA,
and the ensuing chloride flux hyperpolarizes the membrane of the postsynaptic
neurone inhibiting further neuronal activity.
Gabaergic and
Glutamatergic
pathways in the CNS
Endocrine role of
GABA
 There are 3 major classes of GABA receptors:
1. GABA-A
Contain chloride channels and contain different binding
channel. It is an ionotropic receptor
2. GABA-B
Receptors bound to G-proteins, therefore it is a
metabotropic receptor
3. GABA-C
It is also ionotropic with chloride channels, however it
has a different subunit structure from other GABA A.
A, Schematic diagram of the synthesis and transport of
GABA (g-aminobutyric acid) at synapses. GABA is
synthesized in inhibitory neurons from glutamate by the
enzyme glutamic acid decarboxylase (GAD), and is
transported into vesicles by a vesicular
transporter (VGAT). GABA can be released either
vesicularly or non-vesicularly (by reverse transport).
GABA receptors are located at pre- and postsynaptic
sites. GABAB receptors are metabotropic receptors that
cause presynaptic inhibition by suppressing calcium influx
and reducing transmitter release, and achieve
postsynaptic inhibition by activating potassium currents
that hyperpolarize the cell. Reuptake of GABA by
surrounding neurons and glia occurs through the
activity of GABA transporters (GAT).
Subsequently, GABA is metabolized by a transamination
reaction that is catalysed by GABA transaminase
(GABA-T).
GABA receptors differ in subunit composition and
assembly. GABAA and GABAC receptors are closely
related pentameric receptors that carry chloride;
however, whereas GABAA receptors are composed of
combinations of several subunit types, GABAC receptors
are composed of only single or multiple -subunits.
GABAB receptors are metabotropic receptors that exist
as R1a, R1b and R2 isoforms, and are associated with
G proteins. Native GABAB receptors are dimers
composed of one R1 subunit and the R2 subunit.
Composition of GABAA receptors
Receptors are oligomeric assemblies of a large range of
subunits, a1-6, b1-3, g1-3, d, e, p and q
In vitro, the pharmacology of the natural
receptors can be replicated with pentameric
combinations of cloned receptor-subtypes,
provided at least one of each of the ,
abg and d subunits is present, and it is
currently thought that the dominant
stoichiometry in vivo is 2abg.
While the dominant a1b2g2 subtypes are present
in both cerebellum and cortex, the
a2bn g2 and a3bng2/3 assemblies are found
mainly in the cortex and hippocampus,
and the a5b3g2 and a5b3g3 are largely
confined to the hippocampus.
In the mammalian brain,
the major subtype has the
composition 2-a1,2-b2,1-g2.
Gaba and Glutamate are both biosynthesized and broken in patways linked to the
citric acid cycle (Krebs cycle).
Glutamine (from glia)
COOH
COOH
glutamic acid decarboxylase
H2N
GAD
COOH
glutammate
H2N
GABA
transaminases
GABA-T
a-ketoglutarate
citric acid cycle
Succinic semialdehyde
Succinic acid
The metabolism of the principal CNS excitatory and
inhibitory neurotrasmitters is intimately linked.
Biosynthetic Pathway and Metabolism of GABA
An example of an anticonvulsant agent working by preventing this feedback inhibition (succinic acid)
is sodium valproate (Depakin or Divalproex Sodium)
Agonisti, parziali agonisti e antagonisti gabaergici che competono con il sito del GABA-A
GABA
AGONISTI
O
N
5-Aminomethyl-isoxazol-3-ol
COOH
4-Amino-butyric acid
OH
Muscimolo
H2N
H2N
+ diversi AGONISTI
di sintesi
Dicentra cucullaria
GABA-A ANTAGONISTI di
origine naturale
O
O
H
N
H
O
O
O
O
Bicucullina
6-(6-Methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g ]-isoquinolin-5-yl)-6H-furo[3',4':3,4]-benzo[1,2-d][1,3]dioxol-8-one
+ diversi ANTAGONISTI
di sintesi
Ligands of GABA-A receptor,
as allosteric modulators
In addition to the GABA binding site, allosteric modulatory sites for numerous ligands
have been identified on GABAA receptors ( benzodiazepines (BZs), barbiturates,
ethanol, neurosteroids, avermectins, picrotoxin, zinc cations, and loreclezole ),
of which the BZ site has historically been of the most pharmacological interest.
Agonists (positive allosteric modulators) give an increased ion flux, resulting in
a greater inhibitory effect on the postsynaptic neurone,
Inverse agonists (negative allosteric modulators) cause a decrease in the ion flux
in response to GABA,
Antagonists (neutral allosteric modulators), have no effect on the ion channel
response to GABA but will competitively displace other BZ site ligands from the
receptor.
Ligands of GABA-A receptor
Therapeutic effetcs of gabaergic modulation
Agonists of the GABA allosteric site show anxiolytic, sleep inducer and muscle
relaxed effects.
Inverse agonists are anxiogenic.
Antagonists have no effect on anxiety, sleep disorders or muscle contraction
disorder.
Classical BZ drugs for the treatment of anxiety and sleep inducer, such as
Diazepam, are full agonists at the BZ site of the GABA-A receptor with no
subtype selectivity.
Although clinically useful, such compounds often exhibit undesirable effects,
particularly sedation, ataxia, and potentiation with alcohol.
There is also a risk of tolerance and dependence developing with chronic use.
Since, neural inhibition is the principle role of GABA, therefore substances
that block GABA can provoke seizures.
Schematic view of muscle relaxant potential of GABA system
A view of the spinal cord and skeletal muscle showing the action of various muscle relaxants - black lines
ending in arrow heads represent chemicals or actions that enhance the target of the lines, blue lines ending in
squares represent chemicals or actions that inhibition the target of the line.
Some molecular models of allosteric modulators of GABA-A receptors
Allopregnanolone
The 3α-hydroxy ring A-reduced pregnane steroids allopregnanolone and tetrahydrodeoxycorticosterone
have been surmised to enhance GABA-mediated chloride currents, whereas pregnenolone sulfate and
dehydroepiandrosterone (DHEA) sulfate display functional antagonistic properties at GABAA receptors.
β-carboline is a benzodiazepine receptor inverse agonist and can therefore have convulsive, anxiogenic and
memory enhancing effects.
Benzodiazepines enhance the effect of the neurotransmitter GABA) at the GABA-A receptor
Allosteric modulators (agonists) of the GABA-A receptor
Barbiturates
phenobarbital
O
HN
O
HN
NH
O
O
O
pentobarbital
NH
O
5-Ethyl-5-(1-methyl-butyl)-pyrimidine-2,4,6-trione
5-Ethyl-5-phenyl-pyrimidine-2,4,6-trione
S
HN
O
NH
O
Thiopental, more as sodium salt
5-Ethyl-5-(1-methyl-butyl)-2-thioxo-dihydro-pyrimidine-4,6-dione
Butalbital, 5-allyl-5-isobutylbarbituric acid, is a barbiturate with an
intermediate duration of action.
Butalbital is often combined with other medications, such as paracetamol
(acetaminophen) or aspirin, and is commonly prescribed for the treatment of pain
and headache.
The various formulations combined with codeine are FDA approved for the treatment
of tension headaches.
Barbiturate activity
Barbiturates depress the central nervous system, they have a wider and more powerful effect on the
central nervous system than the other sedatives.
The barbiturates can produce varying degrees of depression of the CNS, ranging from mild sedation to
general anesthesia.
In low doses barbiturates have a calming effect, and some of the barbiturates (e.g., phenobarbital) have
demonstrated selective anticonvulsant properties. In moderate doses they produce a drunken euphoric state,
similar to alcohol.
Sedation and sleep result from increased doses, and even higher doses produce surgical
anesthesia.
Because of their ability to produce sedation and decrease sleep latency, barbiturates were popular in the
treatment of insomnia prior to the advent of benzodiazepines.
However, because of the high incidence of tolerance and physical dependence following chronic
use and the relatively high danger of overdose, these drugs are rarely used today for the treatment of anxiety
or sleep disturbances.
Allosteric modulators (agonists) of the GABA-A receptor
R
O
N
O
N
H
O
Glutetimide
O
R = H, 3-Ethyl-3-phenyl-piperidine-2,6-dione
R = NH2, Amino-glutetimide
N
H
O
O
Thalidomide,
RHN
now used as an immunomodulatory drug
O
O
O
O
NH2
Meprobamato
R = H, Carbamic acid 2-carbamoyloxymethyl-2-methyl-pentyl ester
R = isopropile, Carisoprodolo
Allosteric modulators (agonists) of the GABA-A receptor
Benzodiazepines
R
N
N
N
X
O
N
R1
R
N
N
R1
N
X
O
Intermediate derivatives
Metaqualone
N
Cl
H
N CH3
N+
O-
Clordiazepossido
(7-Chloro-5-phenyl-3H-benzo[e][1,4]diazepin-2-yl)-methyl-amine 4-ossido
N+
O
-
Modificazioni chimiche del Clordiazepossido
H
N CH3
N
O
N
Cl
a
Cl
H
N
O
N
O
H+/H2O
b
a)
La funzione imino-metil-aminica non è indispensabile per l’attività
b)
L’ N->O in posizione 4 non è indispensabile per l’ attività
PCl3
H
N
Cl
O
N
The acive metabolite of chlordiazepxide is desmethyldiazepam
desmethyldiazepam
7-Chloro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one
Relazione struttura-attività del nucleo benzodiazepinico
•
L’ azoto in posizione 1 puo’ essere alchilato con gruppi di moderato ingombro sterico o con
funzioni salificabili per migliorare la solubilità in solventi acquosi; la dealchilazione della posizione 1 genera
metaboliti attivi.
R
N
X
O
H
N
CH3
R=
N
-CH2-P(O)(CH3)2
Il FOSAZEPAM,
fosfinil derivato,
è considerato il sale
solubile del DIAZEPAM
Relazione struttura-attività del nucleo benzodiazepinico
•
Il carbonile della posizione 2 non è indispensabile per l’ attività anche se il parziale carattere di doppio
legame dell‘amide rende il ciclo a 7 termini quasi planare con i due aromatici su due piani che
formano un angolo compreso tra 58-86°.
H
N
Cl
Derivato non ossigenato nella posizione 2
O
N
Relazione struttura-attività del nucleo benzodiazepinico
Le posizioni 1,2 possono essere impiegate per la formazione di una ulteriore struttura ciclica.
R
Y
X
N
X'
N
Relazione struttura-attività del nucleo benzodiazepinico
•
La posizione 3 puo’ essere sostituita con gruppi polari e idrofilici, OH, COOH; i 3-idrossi derivati sono
dei metaboliti attivi.
H
N
O
H
N
O
3
Cl
N
R
X
N
-OH
R=
-COOH
or sodium/disodium salt
Relazione struttura-attività del nucleo benzodiazepinico
•
La maggior parte delle benzodiazepine presenta il doppio legame in posizione 4/5, queste posizioni
sono state anche utilizzate per la formazione di un ulteriore struttura ciclica;
H
N
H
N
O
O
5 4
Cl
N
N
X
5 4
R
X
Ketazolam
R
Relazione struttura-attività del nucleo benzodiazepinico
Il sostituente in 5 è un aromatico, generalmente fenilico indispensabile per l’attività, la ulteriore
sostituzione in 2’ con alogeni ne incrementa l’attività.
H
N
5
O
-Cl
X
N
R
2’
R=
-F
Relazione struttura-attività del nucleo benzodiazepinico
L’aromatico della nucleo benzo-diazepincio è sempre sostituito in posizione 7 con gruppi
elettronattattori, Cl, NO2, Br; il farmacoforo fenilico puo’ essere sostituito con l’isostero tiofene.
H
N
O
N
X
X = Cl, F, Br, NO2
S
H
N
O
X
2-bromo-thiophene
N
X = Br
Brotizolam
Relazione struttura-attività del nucleo benzodiazepinico
•
Infine il nucleo 1, 4-diazepinico puo’ essere strutturato in 1,5-diazepinico ma la disposizione
dei due anelli aromatici deve rientrare nei termini indicati precedentemente.
R
N
X
N
O
O
Alcune benzodiazepine di uso terapeutico
Ansiolitici, ipnoinducenti, antiepilettici e miorilassanti
O
N
Cl
N
Diazepam
7-Chloro-1-methyl-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one
Diazepam undergoes oxidative metabolism by demethylation (CYP 2C9, 2C19, 2B6, 3A4, and 3A5),
hydroxylation (CYP 3A4 and 2C19) and glucuronidation in the liver as part of the cytochrome P450
enzyme system.
The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam).
Its other active metabolites include the minor active metabolites temazepam and oxazepam.
Alcune benzodiazepine di uso terapeutico
Ansiolitici, ipnoinducenti, antiepilettici e miorilassanti
H
N
O2N
O
N
Nitrazepam
7-Nitrol-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one
Flurazepam
7-chloro-1-[2-(diethylamino)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one
Flunitrazepam
7-Nitro-5-(2-fluoro-phenyl)-1-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one
About the medical use of benzodiazepines
Diazepam possesses anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant and amnestic
properties.
It is commonly used for treating anxiety, insomnia, seizures, alcohol withdrawal, and muscle spasms.
It may also be used before certain medical procedures (such as endoscopies) to reduce tension and
anxiety, and in some surgical procedures to induce amnesia.
Diazepam has a half-life of 20–50 hours, and desmethyldiazepam has a half-life of 30–200 hours and is
considered to be a long acting benzodiazepine.
Diazepam is metabolised via oxidative pathways in the liver via the cytochrome P450 enzyme system. It
has a biphasic half-life of 1–2 and 2–5 days, and has several pharmacologically active metabolites. The
main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or
nordiazepam).
Diazepam's other active metabolites include temazepam and oxazepam.
These metabolites are conjugated with glucuronide, and are excreted primarily in the urine.
The United States Pharmacopoeia lists diazepam as soluble 1 in 16 of ethyl alcohol, 1 in 2 of chloroform,
1 in 39 of ether, and practically insoluble in water.
Nitrazepam is a hypnotic drug with sedative and motor impairing properties, anxiolytic, amnestic,
anticonvulsant, and skeletal muscle relaxant properties.
Nitrazepam is long acting and is sometimes used in patients who have difficulty in maintaining sleep.
Flunitrazepam is considered to be one of the most potent benzodiazepine hypnotic on effect,
rather than on dose basis; i.e., its hypnotic effect is considered to be one of the most strongly pronounced
of all benzodiazepine hypnotics available.
Abuse of flunitrazepam among drug addicts is considerable and any possession of flunitrazepam without
a valid prescription is illegal.
Alcune benzodiazepine di uso terapeutico
Ansiolitici, ipnoinducenti, antiepilettici e mirilassanti
H
N
O
OH
Cl
N
Cl
Lorazepam
7-Chloro-5-(2-chloro-phenyl)-3-hydroxy-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one
Oxazepam
7-Chloro-5-phenyl-3-hydroxy-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one
Lorazepam is a benzodiazepine drug with short to medium duration of action.
It has all five intrinsic benzodiazepine effects: anxiolytic, sedative/hypnotic, anticonvulsant and muscle
relaxant, to different extents.
It is a powerful anxiolytic.
It is a unique benzodiazepine insofar as it has also found use as an adjunct antiemetic in chemotherapy.
Pure lorazepam is an almost white powder that is nearly insoluble in water and oil.
In medicinal form, lorazepam is mainly available as tablets and a solution for injection but in some locations it
is also available as a skin patch, an oral solution and a sublingual tablet.
Lorazepam injectable solution is administered either by deep intramuscular injection or by intravenous
injection.
The injectable solution comes in 1 mL ampoules containing 2 mg or 4 mg lorazepam.
The solvents used are polyethylene glycol 400 and propylene glycol.
As a preservative, the injectable solution contains benzyl alcohol.
Benzodiazepine di uso terapeutico
Ansiolitici, ipnoinducenti, antiepilettici e mirilassanti
N
N
N
Cl
N
Alprazolam
8-Cloro-6-fenil-1-metil-4H-1,2,4-triazolo-4,3a-1,4-benzo [e]diazepina
•Triazolam, 6(2-chloro-phenyl)-Alprazolam
•Adinazolam, (1-dimethy-amino-methyl)-Alprazolam
•Multiple N-dealkylations lead to the removal dimethyl-aminomethyl side chain
•alpha-hydroxyalprazolam, Esatazolam are the main metabolites
N
N
Cl
N
F
Midazolam
8-Cloro-6-(2-fluorofenil)-1-metil-4H-imidazo-1,5-a-1,4-benzo-[e]diazepina
Alprazolam, also known under the trade names Xanax and Niravam, is a short-acting drug of the
benzodiazepine class.
The first indication for which alprazolam was approved was panic disorder.
It is generally used to treat moderate to severe anxiety disorders, panic attacks, and as an adjunctive
treatment for anxiety associated with clinical depression.
Alprazolam is FDA-approved for the short term treatment (up to 8 weeks) of panic disorder, with or without
agoraphobia.
Alprazolam is very effective in preventing moderate to severe anxiety, essential tremor, panic attacks and
other types of convulsive behaviors.
Triazolam (marketed under brand names Halcion, Novodorm, Songar) is a benzodiazepine
possessing pharmacological properties similar to that of other benzodiazepines, but it is generally only
used as a sedative to treat insomnia.
Insomnia can best be described as a difficulty falling asleep, frequent awakening, early awakenings or a
combination of each.
Triazolam is a short acting benzodiazepine and is sometimes used in patients who have difficulty in falling
asleep.
Short half life hypnotics such as triazolam are not effective in patients who suffer from frequent
awakenings or early wakening due to their very short half life.
Triazolam has a very high risk of dependency with chronic users often taking exceedingly high daily doses.
Midazolam (marketed under brand names Dormicum, Flormidal) is a drug which is a benzodiazepine
derivative.
It has powerful anxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant and sedative
properties.
It is considered a short-acting benzodiazepine, with a short elimination half-life.
It is therefore a very useful drug to use for short minor procedures such as dental extraction.
Because of midazolam's extremely short duration, midazolam is not used for patients who have trouble
staying asleep through the night; moderate to long acting benzodiazepines like temazepam, nitrazepam,
flunitrazepam and lormetazepam are used for those purposes.
Midazolam is also indicated for the acute management of aggressive or delirious patients and also is
sometimes used for the acute management of seizures such as status epilepticus.
Long term use for the management of epilepsy is not recommended however, due to the significant risk of
tolerance which renders midazolam and other benzodiazepines ineffective and as well the significant side
effect of sedation.
Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs.
As of 2010, it is the most commonly used benzodiazepine in anesthetic medicine, because it is shorter
lasting, is more potent, and causes less pain at the injection site.
Summary of benzodiazepines activity and side effects
•The benzodiazepines are currently the most important class of drugs for
treatment of anxiety and sleep disorders.
•Benzodiazepines share the sedative-hypnotic properties, but produce fewer side effects than barbiturates.
•Like barbiturates, benzodiazepines have also been reported to produce anticonvulsant effects.
•In addition, these drugs are used clinically as muscle relaxants, antiepilieptic agents, and to produce
sedation before operative procedures.
•The antianxiety effects of benzodiazepines are more selective than those of other sedative-hypnotics,
they relieve anxiety at lower doses and thus produce minimal sedation and motor impairment.
Side effects of benzodiazepins consider: tolerance and physical dependence,
•amnesia and oversedation such as potentiation of alchool and other drugs.
Design of new ligands of GABA-A receptor
Ó) Inverse agonist of the GABA-A receptor, negative modulator
O
O
O
O
N
N
H
O
N
4-Ethyl-6,7-dimethoxy-9H-b-carboline-3-carboxylic acid ethyl ester
Cl
N
◊ Partial agonist of the GABA-A receptor
Diazepam
Imidazenil
6-(2-bromophenyl)-8-fluoro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide
◊ Antagonist of the GABA-A receptor
O
N
Cl
N
N
N
O
O
Diazepam
N
F
O
Flumazenil
8-Fluoro-5-metil-5,6-diidro-4H-imidazo-1,5-a-1,4-benzo-[e]-diazepin-6-one-3-carbossilico acido etil estere
Other molecular model for GABA-A receptor interaction called “NONBENZODIAZEPINE” or Z-DRUGS
R
N
Pyrrolopyrazine
Bnezodiazepine
Atypical benzodiazepine receptor ligands
•While unselective full agonist BZs such as diazepam are anxiolytics with sedative
side effects apparent at higher doses, the BZ site full agonist zolpidem that has some
binding selectivity for a1-containing receptors over other GABA-A subtypes is a
clinical hypnotic, implicating a1-containing subtypes in the sedative response (2-a1,2-b2,1-g2).
O
CH3
N
N
N
CH3
H3C N
O
N
CN
N
N
Zalepon
N-[3-(3-Cyano-pyrazolo[1,5-a]-pyrimidin-7-yl)-phenyl]-N-ethyl-acetamide
H3C
Zolpidem
N,N-Dimethyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]-pyridin-3-yl)-acetamide
Recently it is confirmed that Zolpidem and Zalepon are agonists “with high affinity
for a1 subunit-containing GABAA receptors, it has very high intrinsic activity and is a
hypnotic that does not induce physical dependence”.
Atypical GABA-A receptor ligands of pyrrolo-pyrazine structure
Eszopiclone
(S)-6-(5-Chloro-2-pyridinyl)- 7-oxo- 6,7-dihydro- 5H-pyrrolo[3,4-b]pyrazin-5-yl- 4-methyl- 1-piperazinecarboxylate
Other ligands of the GABA-A receptor
The metabotropic GABA-B receptors constitute a distinct subclass of receptors
for the inhibitory amino acid GABA (Bowery, 1993).
GABA-B receptors have been shown to interact with G proteins of the Gi/Go family
and to activate different signalling mechanisms, including stimulation of K+
conductance, inhibition of Ca2+ channel activities and modulation of
cyclic AMP formation.
It should be pointed out that the exact location and the functional role of the GABA-B
receptor are still not well defined.
However, it appears to be located on the pre- and postsynaptic
which regulate GABA release.
gabaergic neurons
The metabotropic GABAB receptor
• These receptors are GPCRS
• Largely presynaptic, inhibit transmitters release
• Most important role is in the spinal cord
• Baclofen, an agonist at this receptor, is a muscle
relaxant
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Metabotropic GABA-B receptors
(-) Baclofen was an agonist of the GABA-B receptor
(+) Baclofen is less active
It is believed that Baclofen, acting like GABA, blocks the activity of
nerves within the part of the brain that controls the contraction and
relaxation of skeletal muscle.
Baclofen
Phaclofen
OH
H2N
[3-Amino-2-(4-chloro-phenyl)-propyl]-phosphonic acid
O
H2N
Cl
(R) 4-Amino-3-(4-chloro-phenyl)-butyric acid
OH
O
P
OH
(3-Amino-propyl)-phosphonic acid
OH
O
P
OH
H2N
Cl
Schematic view of muscle relaxant potential of GABA system
Baclofen
A view of the spinal cord and skeletal muscle showing the action of various muscle relaxants - black lines
ending in arrow heads represent chemicals or actions that enhance the target of the lines, blue lines ending in
squares represent chemicals or actions that inhibition the target of the line.
A new class of sleep agents
Ramelteon
In 2005, the FDA approved the melatonin receptor antagonist RAMELTEON for the treatment of insonnia,
rappresenting the first novel mechanism to be approved in 35 years and the only hypnotic not classified
as a controlled substance.
Ramelteon, marketed as Rozerem by Takeda Pharmaceuticals North America, is the first in a new
class of sleep agents that selectively binds to the MT1 and MT2 receptors in the suprachiasmatic
nucleus (SCN), instead of binding to GABA A receptors, such as with drugs like zolpidem,
eszopiclone, and zaleplon.
(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8yl)ethyl]propionamide
Melatonin
Ramelteon is a melatonin receptor agonist with both high affinity for
melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor.
Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1
or MT2 receptors, and high selectivity for human MT1 and MT2 receptors compared
to the MT3 receptor.
The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its
sleep-promoting properties, as these receptors, acted upon by endogenous melatonin,
are thought to be involved in the maintenance of the circadian rhythm underlying the
normal sleep-wake cycle.
Ramelteon has no appreciable affinity for the GABA receptor complex or for
receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline,
acetylcholine, and opiates.
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