GABA MODULATORS

GABA MODULATORSBy Dr .Elza Joy Munjely,JR II,Govt. Medical College ,Kottayam.

Introduction

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

Inhibitory neurotransmitters

GABAGlycine

The GABA system - target of a wide range of drugs active on the CNS-

Anxiolytics , sedative-hypnotics,General anesthetics, and Anticonvulsants

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.

Biosynthesis, Storage and Release

Synthesis

GlutamineGlutamateGABASuccinyl semialdehyde

GlutaminaseGADGABA transaminase

TerminationReuptake into presynaptic terminals and/or surrounding glial cells is the primary mechanism of termination.

RECEPTORS

THREE MAJOR TYPES

GABA AGABA BGABA C

GABA A GABA BTypeIonotropicMetabotropicLocationWidely spread ,mainly GABA ergic interneuronsWidespread,presynaptic & postsynapticSubcellular eventPostsynaptic inhibition by chloride influxPresynaptic inhibition by calcium entryPostsynaptic inhibition by Potassium effluxAgonistGABA,Muscimol,Gaboxadol,BZD,Barbiturates,Steroid anaestheticsGABA,BaclofenAntagonistBicuculline,Gabazine,Flumazenil2- hydroxy-saclofenChannel blockerPicrotoxinNA

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 and domain ( 2 ,2 ,1 )

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.

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

Allosteric modulationThe 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.

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

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.

Transmitter gated chloride channel

Retina,spinal cord,superior colliculus,pituitary

Physiological role is not yet discovered.

GABA C RECEPTORS

DRUGS ACTING ON GABA RECEPTORS

DRUGS ACTING ON GABA A RECEPTORS

DrugsActionGABAEndogenous agonistpromotes chloride influxMuscimolAgonist at GABA A siteBicucullinecompetitive antagonist at GABA A binding sitePicrotoxinBlocks chloride channel noncompetitively;acts on picrotoxin sensitive siteBarbiturateAgonist at allosteric site,prolong GABA action,open chloride channelAlcohol, Inhalational anaesthetics,Propofol Open chloride channel directly,Allosteric facilitation of GABABenzodiazepineAgonist at allosteric BZD sitefacilitate GABA action -carbolineInverse agonist at BZD siteimpede GABA actionFlumazenilCompetitive antagonist at BZD site

DRUGS ACTING ON GABA ARECEPTORS

MUSCIMOLDerived from a hallucinogenic mushroomResembles GABA chemicallyPowerful GABA receptor agonistGABOXADOLSynthetic analogue of GABAPartial agonistDeveloped as a hypnotic drugNow withdrawn

BICUCULLINENaturally occuring convulsant compoundSpecific antagonist that blocks the fast inhibitory synaptic potential in most CNS synapsesGABAZINESynthetic GABA analogueNo therapeutic useExperimental tool

BENZODIAZEPINESPowerful sedative,anxiolytic & anticonvulsant effectSelective potentiation of GABA effect on GABA A receptors.Binds to accessory site on GABA A receptor facilitation of GABA bindingBinding of BZD increases frequency of chloride channel opening -GABA facilitatory action

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

UsesPhenobarbitone in epilepsy Thiopentone in anaesthesia No other barbiturate is used nowAs hypnotic & anxiolytic they have been superseded by BZD

NEUROSTEROIDSEnhance activation of GABA A receptorsAlphaxolone-synthetic neurosteroid developed as an anaesthetic agentPICROTOXINConvulsant Acts by blocking chloride channel asso. with GABA A receptorBlocks postsynaptic inhibitory effect of GABANo therapeutic effect

DRUGS ACTING ON GABA B RECEPTORS

DrugAction

BaclofenSelective agonist2-Hydroxy-saclofenCompetitive antagonist-Hydroxybutyrateweak agonist

DRUGS ACTING ON GABA BRECEPTORS

BACLOFENSelective agonistStructural analog of (GABA) stimulation of the GABAB receptor subtype or inhibiting GABA release. also has CNS depressant actionFor treatment of spasticity & relative motor disordersAlso for treatment of drug dependence

well absorbed (100%) orally excreted primarily unchanged in the kidney thus dose adjustment in renal impairment may be necessary!!!!

2 HYDROXYSACLOFENcompetitive antagonist

GAMMA HYDROXYBUTYRATEOccurs naturally in brain as a side product of GABA synthesisHas found favour with body builders,based on the ability to evoke the release of growth hormone& with party- goers, based on its euphoric & disinhibitory effects

GABA Reuptake & Metabolism inhibitors

DrugActionTiagabineInhibits GABA transporter(GAT 1)VigabatrineInhibits GABA transaminaseValproateInhibits GABA transaminase,succinic semialdehyde dehydrogenase & stimulate Glutamic acid decarboxylase

TiagabineVigabatrinValproateValproate

Gabapentin & PregabalinModify synaptic & nonsynaptic release of GABABind to 2 subunit of voltage gated N-type calcium channel calcium entry in the presynaptic membrane

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