GABAB receptors (see Bettler et al., 2004) are located pre- and postsynaptically, and they are typical G-protein-coupled receptors, but unusual in that the functional receptor is a dimer consisting of two different subunits (see Ch. 3). Apart from minor splice variants, only a single isoform is known-also unusual among G-protein-coupled receptors. GABAB receptors exert their effects by inhibiting voltage-gated calcium channels (thus reducing transmitter release) and by opening potassium channels (thus reducing postsynaptic excitability), these actions resulting from inhibition of adenylyl cyclase.
Transcript of "Gaba Receptor "
DR. NITIN SHINDE
FYR DEPARTMENT OF PHARMACOLOGY
Lokmanya Tilak Municipal Medical
College & GH SION MUMBAI-22
(Basic Understanding Of GABA Receptors And Their Types)
1. Neurotransmitter :- GABA
2. GABA: SYNTHESIS, UPTAKE, AND METABOLISM
3. A,B,C ,… types of GABA receptors.
4. GABA : A receptor
a) GABA –A- structure
b) GABA –A- subunits
c) GABA –A- MOA
5. Extra Synaptic GABA A receptors
6. GABA B receptors
b) Molecular structure of GABA B receptor
c) M.O.A of GABA B receptor
Neurotransmitter :- GABA
• Chief inhibitory neurotransmitter in mammalian central
• Approximately 40 % neurons in mamalian CNS are purely
Synthesis of GABA
GABA: SYNTHESIS, UPTAKE, AND
Synthesized in brain – GABA shunt
A,B,C……Types of GABA Receptor
• Three main types: A, B, and C.
• The GABAA receptor, is a ligand-gated Cl– ion channel,
an "ionotropic receptor.“
• The GABAB receptor is a GPCR.metabotropic.
• The GABAC receptor is a transmitter-gated Cl– channel.Newly
GABAA receptor structure
• It is a multimeric transmembrane
receptor that consists of 5 subunits
arranged around a central Cl− ion
• Members of family of Cys-loop
ligand-gated ion channels (loop
formed by a disulfide bond betn 2
• The receptor is usually located postsynaptically.
However, some isoforms may be found extrasynaptically
• Each subunit is composed of a polypeptide sequence of
approximately 450–630 amino acids (40–60 kDa) with large N-
terminal and smaller C-terminal extracellular domains.
• individual subunits contain four distinct transmembrane(TM)
domains, with the second transmembrane domain (TM2) lining the
• A large intracellular loop
connects the TM3 and TM4
regions providing sites for
by a range of serine, threonine, aspargine & tyrosine
GABAA receptor MOA
• Binding of GABA triggers opening of the Cl− ion pore.
• This drives the membrane potential towards the reversal
potential of the Cl¯ ion which is about –65 mV in neurons,
inhibiting the firing of new action potentials.
• This makes it more difficult for excitatory neurotransmitters to
depolarize the neuron.
• The net effect is typically inhibitory, reducing the activity of
Extrasynaptic GABAA Receptors
• Synaptic GABAA receptors Underlie
• By contrast, extra-synaptic receptors
are usually exposed to low but
GABA concentrations leading to
• Compared to their synaptic counterparts, these show
i. Increased sensitivity to GABA
ii. Reduced propensity to desensitize
iii. More rapid deactivation phase after removal of GABA
Extrasynaptic GABAA Receptors
• The occurrence of tonic GABAA inhibition coincides with the
expression of relatively rare receptor subunits, articularly the
α4, α6, and δ subunits, and as a general rule-of-thumb, δ
subunit-containing receptors are extrasynaptic.
• The subunit can also govern receptor pharmacology:
– extrasynaptic GABAARs are insensitive to benzodiazepine
– but highly sensitive to the GABAAR “super agonist”
Extrasynaptic GABAA Receptors
Studies have begun to identify extrasynaptic GABAARs as
novel targets for a diverse array of endogenous and
clinically relevant agents, including :
• Certain Neuroactive steroids
• Amino acid Taurine
• Several Anesthetic
• Hypnotic agents
• Some Anticonvulsant drugs.
GABAB - discovery
• Baclofen was first synthesized in 1962 by a
chemist Heinrich Keberle and was shown to exert
potent muscle-relaxant and analgesic properties
• . A report from Bowery et al. holds an invaluable
pharmacological tool in elucidating the role of GABAB
receptors in several disorders including epilepsy, cognition
• Bowery and Hudson described a bicuculline insensitive action
of GABA in beclofen which lead to the discovery of GABA B
Heterodimer composed of two similar subunits each with a seven trans-membrane
α-helix (7 TM) topology.
GABA (B) R1 and GABA (B) R2.
Each subunit comprises a large N terminal extracellular domain
followed by 7-transmembrane helicesand an intracellular C-terminus.
GABA (B) R1 binds to ligand and initiates a
conformational change in the receptor complex,
GABA (B) R2 interacts with and transmits this
signal to the intracellular G-protein trimer.
Two GABA (B) R1 isoforms, GABA (B)R1a and GABA (B) R1b, are expressed in
Two “Sushi motifs” are present GABA (B) R1a and absent in GABA (B) R1b.
GABA-ρ subclass ( GABAC)
• A subclass of ionotropic GABA receptors, insensitive to
typical allosteric modulators
• GABAС receptors are exclusively composed of ρ (rho)
subunits that are related to GABAA receptor subunits
• Designated as the ρ subfamily of the GABAA receptors
• These receptors are found in the retina, spinal cord, superior
colliculus, and pituitary.
• Three homologous
ρ-subunits, ρ1 to ρ3,
have now been
• There is only limited evidence that the ρ-subunits co-
assemble with any of the other GABAA receptor subunits.
• The genes encoding the ρ1- and ρ2-subunits are found on
chromosome 6 of man, and are thus distinct from the
clusters of receptor subunit genes which are found on
• Chromosomes 4, 5, 15 and X with the exception of
δ, which is found on chromosome 1.
GABA –C MOA
• Its is ionotropic receptor with action
similar to GABA-A Receptor.
• These receptors, are Cl- pores that are
insensitive to both bicuculline and
• They are designated GABAC in
1984 but An IUPHAR
nomencleature：the term GABAC
be avoided and classifies it as
bicuculline and baclofen-insensitive
GABA receptors as a minor group
APPLICATION OF GABA-A
• BZD RECEPTOR MODULATORS
• ALCOHOL & GABA
• ROLE IN ANTIEPILEPTICS.
• Neuroactive steroid
• Agonists: Bind to the main receptor site - also referred to as the
"active" or "orthosteric" site- and activate it
• Antagonists: Bind to the main receptor site but do not activate it.
• Positive Allosteric Modulators: Bind to allosteric sites on the
receptor complex and affect it in a positive manner, causing
increased efficiency of the main site and thus increase in Cl-
• Negative Allosteric Modulators: Bind to an allosteric site on the
receptor complex and affect it in a negative manner, causing
decreased efficiency of the main site.
• Uncompetitive Channel Blockers: Bind to or near the central pore
of the receptor complex and directly block Cl- conductance.
Ibotenic acid and Muscimol
• Contained in Amanita muscaria/pantherina/gemmata
(hallucinogenic mushroom) with muscarine, muscazone.
• GABAA agonist + potent partial GABAC agonist
• Muscimol is as much as 10 times more potent
• Effects are frequently compared to a lucid dream state.
• Psychoactive dose of muscimol is around 10–15 mg
• Extrasynaptic GABAA agonist
• Increases deep sleep (stage 4).
• BZDs/Z drugs work on the α1 subtype of receptors for the
neurotransmitter GABA -- that's akin to an 'on/off switch' for
the central nervous system.
• On the other hand, gaboxadol works on another subtype,
called α4 -- it's more of a 'dimmer switch' that might help
regulate sleep in a less disruptive way
Various GABAA antagonists
Bicuculline •Competitive antagonist of GABAA receptors
•Utilized in laboratories in the in vitro study of epilepsy
•Routinely used to isolate glutamatergic (excitatory amino
acid) receptor function.
Gabazine •Antagonist at GABAA receptors
•Used in scientific research and has no role in medicine
•Phasic (synaptic) inhibition is gabazine- sensitive, tonic
(extrasynaptic) inhibition is relatively gabazine- insensitive
•Found in various plants, most notably water hemlock (Cicuta
& Oenanthe species)
•Potent noncompetitive GABA receptor antagonist
•Nausea, emesis and abdominal pain within 60 mins of
ingestion. Can lead to tremors, seizures & death
Various GABAA antagonists
Thujone •Found in a number of plants, such as arborvitae
•Used in herbal medicine, mainly for their immune-
system stimulating effects
•Reported to be toxic to both brain and liver cells
•Side-effects include anxiety and sleeplessness,
seizures at high dose
•Poisonous crystalline plant compound
•Found in the fruit (fishberry) of climbing
plant Anamirta cocculus.
•Noncompetitive antagonist for GABAA receptor
- Channel blocker
•Can be used to counter barbiturate poisoning
• Benzodiazepines act at GABAA
receptors by binding directly to a
specific site, distinct from that of
• They do not activate GABAA
receptors directly but rather require
GABA to express their effects; i.e.,
they only modulate the effects of
• Studies of cloned
have shown that the
coassembly of a γ
subunit with α and β
sensitivity to GABAA
Benzodiazepines bind across
the interface between the α
and γ subunits but only to
receptors that contain γ2 and
α1, α2, α3 or α5
BDZ BINDING SITE…
Benzodiazepines (BDZs) bind to the gamma sub-unit of the
GABA-A receptor. Their binding causes an allosteric (structural)
modification of the receptor that results in an increase in GABA
A receptor activity. BDZs do not substitute for GABA, which
bind at the alpha sub-unit, but increase the frequency of channel
opening events which leads to an increase in chloride ion
conductance and inhibition of the action potential
NON BENZODIAZEPINE GABA
• commonly referred to as "Z compounds".
• They include:-
• zolpidem (AMBIEN),
• zopiclone (Not marketed in the U.S.), and
• eszopiclone (LUNESTA), which is the S(+) enantiomer of
• Pyrazolopyrimidine class of
• Zaleplon preferentially binds to the
benzodiazepine-binding site on
GABAA receptors containing the
• P.K - Absorbed rapidly and reaches
peak plasma concentrations in ~1
hour. Its bioavailability is ~30%
because of presystemic metabolism
volume of distribution of ~1.4 L/kg
and plasma-protein binding of
• Metabolised by aldehyde
• Zaleplon (usually
administered in 5-, 10-, or
20-mg doses) has been
studied in clinical trials of
patients with chronic or
• Although the actions of zolpidem are
due to agonist effects on GABAA
receptors and generally resemble those
of benzodiazepines, it produces weak
anticonvulsant effects in experimental
• During U.S. clinical trials, withdrawal
effects within 48 hours of drug
discontinuation occurred at an
incidence of 1% or less. Post-
marketing reports of abuse,
dependence, and withdrawal have been
• zolpidem is approved
only for the short-term
treatment of insomnia.
• Therapeutic doses (5 to
10 mg) zolpidem
residual daytime sedation
or amnesia adverse
or dizziness) is also low.
• Active S(+) enantiomer of
zopiclone. Eszopiclone has no
structural similarity to
benzodiazepines, zolpidem, or
• Eszopiclone is used for the long-
term treatment of insomnia and for
sleep maintenance. It is prescribed to
patients who have difficulty falling
asleep as well as those who
experience difficulty staying asleep,
and is available in (1-, 2-,or 3-
• Eszopiclone received
FDA approval based on
six randomized placebo-
controlled clinical trials
that showed it has
efficacy in treating
transient and chronic
Inverse agonist at BZD Receptor
• Inverse agonists at the BZD site act as negative allosteric
modulators of GABA-receptor function.
• Their interaction with BZD sites on the GABAA receptor can
produce anxiety and seizures.
Sarmazenil •Partial inverse agonist at
the benzodiazepine site.
•It is used in veterinary medicine to reverse
the effects of benzodiazepine sedative drugs
in order to rapidly re-awaken anaethetised
β Carbolines •In addition to their direct actions, these
molecules can block the effects of
•Uses as convelsants.
Negative allosteric modulators at
FLUMAZENIL: A BENZODIAZEPINE
• Flumazenil (ROMAZICON, generic), the only member of this
class, is an imidazobenzodiazepine that behaves as a specific
• Flumazenil binds with high affinity to specific sites on the
GABA-A receptor, where it competitively antagonizes the
binding and allosteric effects of benzodiazepines and other
• Flumazenil antagonizes both the electrophysiological and
behavioral effects of agonist and inverse-agonist
benzodiazepines and B-carbolines.
• Recommended dose 1mg IV . t1/2 of ~1 hour.dose repeated till
• Can be used to reverse the effect of benzodiazepine
overdosage , or to reverse the effect of benzodiazepines such
as midazolam used for minor surgical procedures.
• It has been found to be effective in overdoses of non-
benzodiazepine sleep enhancers - zolpidem and zaleplon.
• Use in hepatic encephalopathy & alcohol intoxication have
yielded mixed results.
• Used as a PET radioligand labeled with carbon-11 to visualize
the distribution of GABAA receptors in brain.
• Flumazenil is not effective in single dose overdoses with either
barbiturates or Tricyclic antidepressants rather it may cause
seizures in patients poisoned with TCA’S.
Barbiturates also facilitate the actions of GABA -A at multiple sites in
the central nervous system, but—in contrast to benzodiazepines—they
appear to increase the duration of the GABA-gated chloride channel
openings. At Higher concentrations, barbiturates directly increase
chloride ion conductance.
• An analogue of valeric acid
• Believed to affect the function of the neurotransmitter GABA in
the human brain by inhibition of GABA transaminase.
• Other mechanisms of action
Blocks the voltage-gated Na+ channels
Blocks T-type Ca++ channels.
Inhibits the enzyme histone deacetylase 1
• Manic episodes associated with bipolar disorder.
• As an anticonvulsant in
Absence seizures Juvenile myoclonic epilepsy
Tonic -clonic seizures Posttraumatic epilepsy
Complex partial seizures Lennox-Gastaut syndrome
• Valproic acid is cytotoxic to many different cancer types
through its action as a histone deacetylase inhibitor.
• Being tried in multiple, myeloma, glioma, melanoma, breast
cancer, cervical cancer and ovarian cancer.
• VIGABATRIN is a “suicide
inhibitor” of GABA transaminase.
• It blocks the conversion of GABA to
succinic semialdehyde,resulting in
high intracellular GABA
concentrations and increased
synaptic GABA release.
• Primary indication for vigabatrin
treatment of simple and complex
partial seizures but it can also be
used for generalised seizures.
Other Uses – Drug refractory
epilepsy and infantile spasm.
Dose:- 2 gm/ day .
sedation ,Amnesia ,Weight gain
In 1% of cases visual field
defects due to peipheral retinal
• Tiagabine (GABITRIL) is a
derivative of nipecotic acid
• Approved by the FDA as
adjunct therapy for partial
seizures in adults.
• Tiagabine inhibits the GABA
transporter, GAT-1, and thereby
reduces GABA uptake into
neurons and glia.
• Paradoxically, tiagabine has
been associated with the
occurrence of seizures in
patients without epilepsy
• Its contraindicated in
Other side effects – Sedation,
fatigue, tremors and confusion.
Dose:- 20-60 mg per day in 3
to 4 equally divided doses.
GABAPENTIN & PREGABALIN
• Gabapentin (NEURONTIN, others) and
pregabalin (LYRICA) are anti-seizure drugs
that consist of a GABA molecule covalently
bound to a lipophilic cyclohexane ring or
• Pregabalin increases neuronal GABA levels
by producing a dose-dependent increase
in glutamic acid decarboxylase activity.
• Gabapentin & pregabalin bind to the α2δ
(alpha2delta) subunit of the voltage-
dependent calcium channel in the central
nervous system and decrease the synaptic
release of glutamate..
suggest that they
also function as
• P.K - Gabapentin and
pregabalin are absorbed
after oral administration . It
is neither metabolised nor
bound to plasma proteins
and are excreted unchanged,
mainly in the urine.
• Their half-lives,
approximate 6 hours.
• These compounds have no
known interactions with
other anti-seizure drugs.
Therapeutic Uses: Drug resistant partial
seizures & G.T.C . also is being used for the
treatment of migraine, chronic pain, and
bipolar disorder. FDA Approves Lyrica
(Pregabalin) for Treatment of Neuropathic
Pain in 2005.
Side effects :- Somnolence, dizziness, ataxia,
Dose – 200-300 mg TDS.
Role OF GABA RECEPTORS IN
Anaesthetics primarily act by either enhancing inhibitory
signals or by blocking excitatory signals
• Currently, there are 5 major
inhalational and 5 intravenous
anesthetics used to induce or
maintain general anesthesia.
• Inhalational:Nitrous Oxide,
Isoflurane, Sevoflurane, Desflurane
• Intravenous: Propofol, Etomidate,
Ketamine, Methohexital and
Of these 10 general anesthetics, except
ketamine, nitrous oxide and xenon
other7 general anesthetics and
sedatives like midazolam, diazepam
and lorazepam share a common target
and mechanism of action,i.e. they all
enhance the function of GABA-A
• The extrasynapic α5ß3γ2 receptor in hippocampus is probably
assosciated with amnestic action of anaesthetic.
• Those receptors having δ subunit s at ventrobasal thalamic
nucleus may be linked to intruding reversible loss of
consciousness during anaesthesia.
• Since general anaesthetics are hydrophobic and need to access
the CNS they target hydrophobic pockets within the
transmembrane domains of the receptor.
Single amino acids determine i.v.
anaesthetic activity ?
• If GABA-A receptors are important targets for general
anaesthetics,are all receptors equally sensitive to their effects?
or are certain subunit combinations more sensitive than others?
• Etomidate which demonstrates selective effects for receptors
containing certain subtypes of the ßsubunit. For example,
receptors containing ß2or ß3, but not ß1subunits are
particularly sensitive to the modulatory effects of this
anaesthetic.4 Studies using a molecular techniques
demonstrated that the selectivity of etomidate maps to a single
amino acid located within the second transmembrane domain
(TM2) of the b subunit (asparagine for ß2 and ß3, and serine
for ß1 subunits). Exchanging the asparagine for serine at ß2
increased the sensitivity of etomidate.
A binding site for volatile anaesthetics?
• The effects of volatile agents on GABA-A receptor activity are also
influenced by a single amino acid. (serine) is located within the TM2
region in the α subunit.
• Subsequent studies demonstrated that the volume of this amino acid
correlated with the activity of volatile anaesthetics on GABA-A
receptors. Specifically, substitution with small volume amino acids
enhanced the potentiating activity of isoflurane,halothane, and
chloroform, whereas the presence of bulkier amino acids reduced
• Use of volatile agents of differing size (isoflurane, 144 A ° ;
halothane, 110 A ° , and chloroform, 90 A ° ) led to the proposalthat
the four amino acid residues from the extracellular end of TM1, TM2,
TM3, and TM4 domains of the a subunit contribute towards an
anaesthetic binding pocket for volatile agents
Synthesized in the central and peripheral nervous system, especially in
myelinating glial cells, from cholesterol or steroidal precursors.
• These include pregnenolone (PREG) and
dehydroepiandrosterone (DHEA), their sulfates, and reduced
• Neurosteroids have a wide range of potential clinical applications
from sedation to treatment of epilepsy and traumatic brain injury.
• Allopregnanolone and tetrahydrodeoxycorticosterone have
been surmised to enhance GABA-mediated Cl¯ currents,
whereas pregnenolone sulfate & dehydroepiandrosterone
(DHEA) sulfate display functional antagonistic properties at
• Ganaxolone, an analog of the endogenous
neurosteroid allopregnanolone, is under investigation for the
treatment of epilepsy and was effective in the treatment of
partial seizures in adults and was tolerated.
This animation shows one model for how neurosteroids may increase Cl–
flux through a GABA-A receptor. Binding of the neurosteroid (ALLO)
allows a protein kinase C (PKC) phosphorylation site to become
accessible. Phosphorylation of the channel increases flux through the
channel, allowing more Cl– ions to flow through the channel in the
presence of GABA than when the channel is activated by GABA without
prior phosphorylation. The top of this animated gif shows how the
channel, the ligands, and G protein-activated PKC may be interacting at
the plasma membrane. The bottom of the animation shows how these
interactions affect the current trace recorded using electrophysiological
techniques. In the current trace, the size of the signal is smaller in the
absence of neurosteroid compared to the size of the signal after exposure
to neurosteroid and subsequent phosphorylation of the channel.
Neurosteroid general anaesthetic.
A study 1987 found the primary
mechanism for the anaesthetic
action of alfaxalone to be
modulation of neuronal cell
membrane chloride ion transport,
induced by binding of alfaxalone
to GABAA cell surface receptors.
It is licensed for use in both dogs
Unlike some of its predecessors
alfaxalone is not associated with
histamine release and anaphylaxis.
• A 1994 study found that
alfaxalone binds to a
different region of this
• Alfaxalone is metabolised
rapidly in the liver.
Alfaxalone has a very short
plasma elimination half-life
in dogs and cats
OTHER NEUROACTIVE STEROIDS
•Proved to be a useful anaesthetic drug with a
good safety profile.
•But was painful and irritating when injected
probably due to poor solubility
•Withdrawn from human use due to rare but
serious toxic reactions, but is still used in
•Around three times more potent than althesin
without the toxicity problems.
•Withdrawn because animal studies suggested
• Ingestion of ethanol results in a
dose-dependent reduction of
central nervous system (CNS)
• For several decades, it was
presumed that this CNS
depression was due to a major
effect of ethanol is through
BZD receptors on GABA.
• But, a lack of ethanol’s effect
on GABA responsiveness from
isolated neurons with this
receptor subtype discontinued
• Direct action of ethanol on
α4β3δ or α6β3δ selectivity for
separate GABA mimetic action
is proved today.
NEUROSTEROID INVOLVEMENT IN THE
GABAMIMETIC PROFILE OF ETHANOL
Following ethanol consumption there is activation of the hypothalamicpituitary-
adrenal (HPA) axis (denoted by the darkened arrows), ethanol increases neurosteroid
precursors from the adrenal, which in turn results in
increased neurosteroids in brain . Since neuroactive steroids enhance GABA
responsiveness (Lambert et al, 2001, 2003; Paul and Purdy, 1992), it is proposed that
the ethanol-induced enhancement of neurosteroid presence in brain synergizes
theeffect of GABA released by ethanol (Criswell and Breese, 2005).
ROLE OF GABA IN ALCOHOL
Thaugh benzodiazepines have been the primary treatment
modality for alcohol withdrawal.
A growing number of preclinical and clinical studies suggest that
the anticonvulsants like gabapentin m
Two RCT – First (n=60) and second (n=21) proved that
gabapentin was significantly more effective than placebo for
prevention of alcohol withdrawal symptoms
But except insomnia.
Other drugs which are currently investigated for alcohol
withdrawal effect are –Baclofen and GHB.
GHB (Gamma hydroxy butyric acid)
Gamma-hydroxybutyric acid (GHB)
acid (GABA) that has been used in
research and clinical medicine for
is a naturally occurring analog of
GHB (Gamma hydroxy butyric acid)
• GHB usually exists either as a free acid, or as a sodium salt. The sodium
salt is called Sodium Oxybate
• and is soluble in water and methanol.
• GHB as is used to treat cataplexy and excessive daytime sleepiness in
patients with narcolepsy.
• GHB has at least two distinct binding sites in the CNS.
– Agonist at the newly-characterized GHB receptor, which is excitatory
• Weak agonist at the GABAB receptor, which is inhibitory. Previously used
as an anesthetic in 1960s but
• was withdrawn due to its side effects like seizures and
• coma. Due to its euphoric effects, it is nowadays used as
• ‘POTENNTIAL ABUSIVE DRUG’
NEGATIVE POINTS POSITIVE POINTS
Rave drug Can be used in narcolepsy
Date rape drug Tried for alcohol withdrawal
Excellent dilator of cervix
Euphoria & crime Can be used as an
GHB Rage or reprive?
Derivative of GABA (β-
It is primarily used to
treat spasticity. In disorders like
However its relatively
ineffective in stroke ,
Cerebral palsy and rheumatic
Tolerance does not develop -
baclofen retains its therapeutic anti-
spasmodic effects even after years
• Primary site is possibly the spinal cord
where it depresses both polysynaptic
and monosynaptic reflexes
• Also used in tardive dyskinesia and
• ADR - Sedation (less than BZDs),
• Baclofen can be delivered directly into
the space around the spinal cord by use
of a surgically implanted pump and an
Excreted unchanged in
urine with t1/2- 3 to 4 hrs
Dose -10 to 25 mg
• β-Phenyl-γ-aminobutyric acid is a derivative of GABA.
• Binds the GABAB metabotropic receptor.
• The addition of a phenyl group in the β position allows
phenibut to cross the blood brain barrier.
• Only the R enantiomer is biologically active
• Sold as a dietary supplement in the United States, while
in Russia it is sold as a neuropsychotropic drug.
• Structurally similar to baclofen & phenylethylamine.
– Pharmacological effects of phenibut are similar to baclofen,
but less potent.
– Additionally, can function as a phenylethylamine receptor
– Furthermore, phenibut has been shown to enhance levels of
• Has anxiolytic effects in both animal models and in humans.
• Used to treat a wide range of ailments including post-traumatic
stress disorder, anxiety, and insomnia.
• It has been reported by some to possess neurotropic actions for
its ability to improve neurological functions,
• ADR - Sedation
Saclofen & Phaclofen
• These are competitive antagonist at GABAB receptor.
• This drug is an analogue of the GABAB agonist Baclofen.
• The action of saclofen on the CNS is understandably modest,
because G-proteins rely on an enzyme cascade.
• However, in animal experiments, saclofen is paradoxically
observed to have an antiepileptic effect.
• Analog and prodrug of GABA used in the treatment of
• Agonist at both the GABAA and GABAB receptors.
• Approved for either monotherapy or adjunctive use in the
treatment of epilepsy—specifically, generalized tonic-clonic,
myoclonic, partial, and Lennox-Gastaut syndrome seizures—
in both children and adults
• Also being investigated for
– Parkinson's disease
– Anxiety disorder
with various levels of success.
• Tolgabide - analogue of progabide and acts similarly to it as a
prodrug of GABA, and therefore as an indirect agonist of the
• Dietary supplement formed by combining
niacin with GABA.It was developed in
the Soviet Union in 1969 by the All-Union
Vitamins Scientific Research Institute
• Crosses BBB and is hydrolyzed into GABA
and niacin. The released GABA would
activate GABA receptors potentially
producing an anxiolytic response
• The second released component, niacin acts
as a strong vasodilator, which might be useful
for the treatment of migraine headaches
In Russia, Picamilon is used for treatment of
1. Ischemic stroke
4. Senile psychosis
5. Alcohol intoxication
7. Craniocerebral trauma
9. Primary open-angle glaucoma
GABA –C AGONIST
• CACA – C Amino caproic acid . Weak agonist.
• TACA – Trans isomer of CACA.strongest agonist at GABA –
• R- CAMP:- Recemic mixture of C-AMP acts as agonist .
TPMPA, Selective GABA-C
• Tetrahydropyridine ring of isoguvacine was
unfavourable for interactions with GABAB
receptors, while the
• methylphosphinic moiety of 3-APMPA was
unfavourable for interactions with GABA-A
receptors led to the synthesisof TPMPA
which incorporates both the
tetrahydropyridine and methylphosphinic
acid moieties in the one compound.
• TPMPA has been used to provide evidence
of functional GABAC receptors in the rat
disinhibition , in
cells in the gut
secretion and in rat
spinal cord .
• TPMPA has been
shown to enhance
memory in chicks .
• Recombinant receptor technology. The cloning of ρ1 and ρ2
cDNAs from a human retinal library enabled expression of
receptors in Xenopus oocytes that showed the characteristics
expected of GABAC receptors .
• GABAC receptors are expected to mediate the lateral
inhibition of light responses and have been shown to inhibit
transmitter release at bipolar cell terminals.
Section III Herbal Preperations and
• Many herbal medicines are used to influence brain function in
order to treat anxiety, cognitive disorders, and insomnia
involving GABA receptor.
• Usually Herbal products act as second order modulators
i.e.they enhance the effect of first order modulators.
• GABA itself is an important plant constituent, and
thus it should not be surprising that plants contain a
range of other chemicals that can influence GABA
First isolated from the plant Dicentra
cucullaria and subsequently from a
variety of Corydalis,Dicentra, and
Competitive antagonist of GABAA
•Utilized in laboratories in the in
vitro study of epilepsy
•Routinely used to isolate glutamatergic
(excitatory amino acid) receptor function.
Picrotoxin is an equimolar mixture of
picrotoxinin and picrotin isolated from
Anamirta cocculus and related poisonous
plants of the moonseed family.
Picrotoxinin is relatively nonspecific in that
it is a potent antagonist at GABA-A and
GABA-C, moderate at glycine, and weak at
Can be used to counter barbiturate poisoning
It is clear that bicuculline and picrotoxinin
act at different sites to antagonize GABA.
• Muscimol is one of the most widely
used agonists in the investigation of
ionotropic GABA receptors.
• It is a more potent agonist at GABA-
C receptors than at GABA-A
• The agonist action of muscimol at
GABA-C receptors is not blocked by
bicuculline but is sensitive to
• (Gaboxadol) is a conformationally
restricted analogue of muscimol with
analgesic and sleep-promoting
It was investigated for the treatment
of insomnia, but was recently
withdrawn from phase III clinical
trials due to efficacy and side-effect
Apigenin – GABA Receptor Modulator
• Common flavonoid found in a range of
plants, including chamomile
• The chamomile tea used in treatment
for insomnia and anxiety led to
investigations of its active constituents,
including apigenin.Apigenin was found
to have anxiolytic properties,and it
competitively inhibited the binding of
flunitrazepam to brain membranes
• Enhancement of the diazepam-induced
positive allosteric modulation of GABA
responses by lower concentrations of
apigenin , described as a
Epigallocatechin gallate (EGCG)
• Epigallocatechin gallate (EGCG) is the
major polyphenol in green tea (Camellia
• Studies on α1ß2γ2GABA-A receptors
showed that EGCG at low
concentrations has a potent second-
order modulatory action on the first-
order modulation by diazepam ( more
• In well-controlled epidemiological
studies it alters brain-aging processes
and to serve as possible neuroprotective
agents in progressive neurodegenerative
e.g. Parkinson’s and
Hispidulin and Related Flavonoids
• Hispidulin (the 6-methoxy derivative of
• apigenin) was isolated together with apigenin from
• Salvia officinalis (sage) recently using a benzodiazepine binding assay-
• Hispidulin was some 30 times more potent than apigenin in displacing
• Used in herbal medicine to assist memory.
• An extract of Salvia lavandulaefolia (Spanish sage) has
been shown to enhance memory in healthy young volunteers.
SCENARIO & FUTURE
GAD 65 OR GAD 67 ?
Knockout of GAD65 has major impact on synaptic
GABA synthesized from astrocyte-derived
• Two isoforms : GAD- 65 & GAD- 67
• GAD65 is crucial for maintenance of biosynthesis of synaptic
GABA particularly by direct synthesis from astrocytic
glutamine via glutamate.
• The GAD67 was found to be important for synthesis of
GABA from glutamine both via direct synthesis and via a
pathway involving mitochondrial metabolism.
GENE ORGANISATION OF
The majority of genes
coding for the
subunits are organized
into four clusters on
chromosomes 4, 5, 15,
and X in the human
analysis of GABA
receptor was simplified
after introduction of
animal models in which
particular GABA- A
receptor subunits are
(knock out) or
mutated ( knock in).
α6 Motor impairing action of
mice on rota rod to
ß3 Die in neonatal period.
γ2 Sleep time was prolonged.
No action of
δ Increased sleep time and
convulsions.No action of
GENE KNOCKOUT & KNOCK IN
GABA – AS IMMUNOMODULATOR
• In lymphocytes,exposure to GABA reduced but did not
abolish the transient increase in the intracellular calcium
concentration that was associated with activation of the cells
(Alam et al.2006).
• GABA activated GABA-A ionchannel currents in T cells and
macrophages (Bjurstom et al. 2008; Bhat et al. 2010;
• GABA application resulted in decreased cytokine secretion
and T cells proliferation (Mendu et al. 2011)
GABA – AS IMMUNOMODULATOR
• GABA appears to have a role in autoimmune diseases
• like MS, type 1 diabetes and rheumatoid arthritis and
maymodulate the immune response to infections
(Bhat et al. 2010; Mendu et al. 2011; Soltani et al. 2011;
Tian et al. 2011; Wheeler et al. 2011).
• Has even a role in Alzheimer disease, stroke and
traumatic brain injury (Popovich and Longbrake 2008;
Schwartz and Shechter 2010)
Role of GABA – IN TYPE- I DM
• Currently a trial with hypothesis that GABA, a naturally
occurring substance, has the potential to reduce the
inflammation and protect the pancreatic beta cells from
• GAD-alum may contribute to the preservation of residual
insulin secretion in patients with recent onset, Type I Diabetes.
• condition :Type I Diabetes
• Drug: Glutamic Acid Decarboxylase in alum formulation
• Status :-Phase 1
GABA & SCHIZOPHRENIA
• In subjects with schizophrenia, impairments in working
memory are associated with dysfunction of the dorsolateral
prefrontal cortex (DLPFC).
• This dysfunction appears to be due, at least in part, to
abnormalities in Gamma-aminobutyric acid (GABA)-mediated
• Various experimental findings suggest that schizophrenia is
associated with alterations in inhibitory inputs from SST/NPY-
containing and CCK containing subpopulations of GABA
neurons and its signaling via certain GABA-A receptors that
mediate synaptic (phasic) or extrasynaptic (tonic) inhibition .
GABA-B Receptor Complex Target
for Tumor Therapy
A positive correlation between
B2 (minor b1)expression and that
of thyroid tumors is seen.
GABAB1 immunostaining of
human ductal breast cancer
tissues (from patents shows
Intensive b unit staining in the
cytosol and less frequently in the
INTERVENTION CONDITION STATUS
1. GAD-Alum Juvenile onset type-1
PHASE – 1 A
2. Merck L-830982
Schizophrenia PHASE – 2.
3. Pregabalin Pain after posteriar
PHASE - 4
4. Vigabatrin Coacaine abuse PHASE -2 A.
5. Gabapentin Smoking PHASE – 1.
6. Lomazenil ALCOHOL ABUSE PHASE -1.
Trial scenario related to GABA…
• Despite the overwhelming representation of the
GPCRs in the human genome, it is the ionotropic
receptors which achieved most visibility till today.
The paucity of molecular heterogeneity exhibited by the
GABA-B receptors has proved problematic for specific drug
• Pharmacologists had to wait till gene knockout tecnique and
readymade animal models became available till early 2000.
• The next decade will undoubtedly prove
Exciting with these recent genetic tools in hand...........