Gaba modulators

1. GABA
MODULATORS
By
Dr .Elza Joy Munjely,
JR II,
Govt. Medical College ,Kottayam.

2. Introduction
• Gamma Amino Butyric Acid (GABA) - major
inhibitory neurotransmitter of the mammalian CNS.

3. Inhibitory neurotransmitters
• GABA
• Glycine

4. The GABA system - target of a wide range of
drugs active on the CNS-
• Anxiolytics ,
• sedative-hypnotics,
• General anesthetics, and
• Anticonvulsants

5. Discovery
• In 19th century – was known as a metabolite of plant
and microorganisms
• In early 20th century - was isolated as an amino acid
in the brain of mouse through paper
chromatography.
• In 1950 Robert and Frankel discovered GABA in
human brain.

6. Biosynthesis, Storage and
Release

7. Synthesis

8. Glutamine
Glutamate
GABA
Succinyl semialdehyde
Glutaminase
GAD
GABA transaminase

10. Termination
• Reuptake into presynaptic terminals and/or
surrounding glial cells is the primary
mechanism of termination.

11. RECEPTORS

12. THREE MAJOR TYPES
I. GABA A
II.GABA B
III.GABA C

13. GABA A GABA B
Type Ionotropic Metabotropic
Location Widely spread ,mainly GABA
ergic interneurons
Widespread,presynaptic &
postsynaptic
Subcellular event Postsynaptic inhibition by ↑
chloride influx
Presynaptic inhibition by ↓
calcium entry
Postsynaptic inhibition by
↑Potassium efflux
Agonist GABA,Muscimol,Gaboxadol,B
ZD,Barbiturates,Steroid
anaesthetics
GABA,Baclofen
Antagonist Bicuculline,Gabazine,Flumaze
nil
2- hydroxy-saclofen
Channel blocker Picrotoxin NA

14. GABA A RECEPTORS
• Ligand gated ion channel
• Distributed throughout the brain.
• It is a heteropentamer, made of five subunits .
• Ligand binds at the interface between α and β
domain ( 2 α,2 β,1 γ)

16. • Different types of GABA A receptors present-
depending on the type of subunit .
• Subunits – alpha(1-6), beta(1-3), gamma(1-3), delta,
epsilon, pi, theta and rho.
• Different types of GABA A receptors - present in
different regions of the brain , at different levels of
development.

17. GABA A receptor when activated, an increase in the
conductance.
Increase in the influx of Cl- ions causing membrane
hyperpolarization.
Increase in the threshold for generating action potential.
Inhibitory action

18. • Allosteric modulation
The site where modulators bind is different from the
site of binding of GABA agonist – known as
“allosteric” site . Modulator - “allosteric modulator”.
The modulator has no activity of its own.
• Positive Allosteric Modulation: ligand binds
allosteric site and enhance the action of
neurotransmitter. E.g.BZD
• Negative Allosteric Modulation: ligand binds to the
allosteric site while an agonist is also bound and the
channel opens less frequently. E.g. Bicuculline.

19. • G-protein coupled receptor.
• Dimer of two, seven transmembrane spanning subunits
held together by a coil – coil interaction btw their C-
terminal tails.
• Activation of receptors occurs when GABA binds to the
extracellular domain of the B1 subunit which produce an
allosteric change in the B2 subunit which couples to the G-
protien
• Widely distributed throughout the CNS.
GABA B RECEPTORS

21. • Located both pre- and post-synaptically.
• Presynaptically- auto-receptor. Inhibits voltage gated
calcium channels,thus decrease neurotransmitter
release.
• Postsynaptically – inhibitory – long lasting
hyperpolarization by activating K+ channel.

22. • Transmitter gated chloride channel
• Retina,spinal cord,superior colliculus,pituitary
• Physiological role is not yet discovered.
GABA C RECEPTORS

23. DRUGS ACTING ON
GABA RECEPTORS

24. DRUGS ACTING ON GABA A RECEPTORS
Drugs Action
GABA Endogenous agonist→promotes chloride influx
Muscimol Agonist at GABA A site
Bicuculline competitive anta
gonist at GABA A binding site
Picrotoxin Blocks chloride channel noncompetitively;acts on picrotoxin sensitive
site
Barbiturate Agonist at allosteric site,prolong GABA action,open chloride channel
Alcohol,
Inhalational
anaesthetics,Propo
fol
Open chloride channel directly,Allosteric facilitation of GABA
Benzodiazepine Agonist at allosteric BZD site→facilitate GABA action
β -carboline Inverse agonist at BZD site→impede GABA action
Flumazenil Competitive antagonist at BZD site

25. BENZODIAZEPINES
• Powerful sedative,anxiolytic & anticonvulsant
effect
• Selective potentiation of GABA effect on
GABA A receptors.
• Binds to accessory site on GABA A receptor →
facilitation of GABA binding
• Binding of BZD → increases frequency of
chloride channel opening -GABA facilitatory
action

28. BARBITURATES
• Binds to barbiturate binding site on GABA A
chloride channel.
• increase the lifetime of chloride channel opening
induced by GABA → potentiate GABA ergic
inhibition - GABA facilitatory action
• At high conc. Barbiturates directly increase chloride
conductance- GABA mimetic action
• Enhance BZD binding to their receptors

30. DRUGS ACTING ON GABA B RECEPTORS
Drug Action
Baclofen Selective agonist
2-Hydroxy-saclofen Competitive antagonist
γ-Hydroxybutyrate weak agonist

31. GABA Reuptake & Metabolism
inhibitors
Drug Action
Tiagabine Inhibits GABA
transporter(GAT 1)
Vigabatrine Inhibits GABA transaminase
Valproate Inhibits GABA
transaminase,succinic
semialdehyde
dehydrogenase & stimulate
Glutamic acid decarboxylase

32. Tiagabine
Vigabatrin
Valproate

33. Gabapentin & Pregabalin
• Modify synaptic & nonsynaptic release of
GABA
• Bind to α2δ subunit of voltage gated N-type
calcium channel → ↓calcium entry in the
presynaptic membrane

34. THANKYOU