GABAA receptor agonist
Drug class
Gaboxadol (THIP), a well-known GABAA receptor agonist andhypnotic.
Class identifiers
Synonyms	GABAA agonist
Use	Seizures,insomnia,hallucinogenic effects
Mechanism of action	GABAA receptoragonism
Biological target	GABAA receptor
Chemical class	GABA analogues and others
Legal status

AGABA_A receptor agonist is adrug that acts as anorthostericagonist of theGABA_A receptor, the majorsignalingreceptor of theinhibitoryneurotransmitterγ-aminobutyric acid (GABA).^[1][2][3]

Themechanism of action of GABA_A receptor agonists is unlike that ofGABA_A positive allosteric modulators, includingbenzodiazepines,Z drugs,barbiturates,neurosteroids, andalcohol, which instead act viaallosteric regulatory sites to potentiate GABA_A receptor function.^[4][3] GABA_A receptor agonists have different effects from those of GABA_A receptor positive allosteric modulators.^[5][6][7][8]

Examples of GABA_A receptor agonists include GABA itself,γ-amino-β-hydroxybutyric acid (GABOB),muscimol (found inAmanita muscariamushrooms),gaboxadol (THIP), andprogabide, among others.^[1][2][3] High-efficacy GABA_A receptor agonists have been found to producesedative,hypnotic,anticonvulsant, andhallucinogenic effects, among others.^{[9][10][11][12]} The structural requirements for GABA_A receptor binding and activation have been found to be very strict, so relatively few high-efficacy GABA_A receptor agonists are known.^[2][13] No fullyselective GABA_A receptor agonists, for instance lacking any additional activity at the closely relatedGABA_A-ρ and/orGABA_B receptors, are currently known.^[14]

GABA_A receptor agonists are generallyGABA analogues andderivatives.^[1][2] Muscimol, aconformationally restrained analogue of GABA, was among the first GABA_A receptor agonists to be identified.^[15]

γ-Aminobutyric acid (GABA) is the majorinhibitoryneurotransmitter in thecentral nervous system.^[6][16][17] It is present in about 25 to 50% ofneurons in thebrain.^[17] The neurotransmitter acts as anon-selectiveagonist of all three types ofGABA receptors, including theGABA_A receptor,GABA_B receptor, andGABA_A-rho receptor (GABA_C receptor).^[6][16] GABA is available as anover-the-countersupplement and is often taken for self-treatment ofinsomnia andanxiety.^[18][19] However, GABA is highly susceptible tometabolism, has a very shortelimination half-life, and is unable to cross theblood–brain barrier.^[18][19] As such, the therapeutic benefits ofexogenous GABA are questionable.^[19]

γ-Amino-β-hydroxybutyric acid (GABOB) is a closeendogenousanalogue of GABA found in the humanbrain.^[20] It acts as a dualGABA_A andGABA_B receptoragonist.^[21] The drug hasanticonvulsant effects and has been used in the treatment ofepilepsy under brand names like Gamibetal in some countries throughout the world.^[22][20][23]

Muscimol is analkaloid found inAmanita mushrooms such asAmanita muscaria (fly agaric).^[10][15][24] It is aconformationally constrainedderivative of GABA.^[15][25] The drug is a highlypotentGABA_A receptorfull agonist.^[10][15] However, it is a selective or preferential agonist ofextrasynapticδ subunit-containing GABA_A receptors.^[10][26][27] The drug also acts as a potentGABA_A-ρ receptorpartial agonist and weakGABA reuptake inhibitor.^[10][15][25] Muscimol is asedative andhallucinogen.^[10][28][29]Ibotenic acid, another alkaloid found inAmanita mushrooms, is aneurotoxin but functions as aprodrug of muscimol and has similar effects.^[30][28][25] Muscimol has served as the basestructure for development of manysynthetic GABA system modulators, including GABA receptor modulators andGABA reuptake inhibitors.^[5][31] The compound has been usedrecreationally as a hallucinogen and has become increasingly used atlow doses for claimed therapeutic benefits, such assleep improvement.^{[10][32][33][34]}

Gaboxadol (THIP) is asyntheticderivative ofmuscimol which acts as apotentGABA_A receptorpartial agonist.^[7][8][11] However, it is a selective or preferentialsupramaximal agonist ofextrasynapticδ subunit-containing GABA_A receptors.^[2][7][9] The drug is also a potentGABA_A-ρ receptorantagonist.^[14] Gaboxadol has improvedselectivy anddrug-like properties compared to muscimol.^{[7][15][5][11]} It hassedative,hypnotic, and, at high doses,hallucinogenic effects.^[8][2][11] The drug was developed for treatment ofinsomnia and other conditions.^[8][2][11] It was found to be effective in the treatment of insomnia, with advantageous properties compared to other hypnotics, such as increasedslow wave sleep (deep sleep).^[8][2][35] Gaboxadol completedphase 3clinical trials for this indication.^[36] However, it was discontinued for various reasons, most notably a narrowtherapeutic index with high rates of hallucinogenic effects at supratherapeutic doses.^[37][38][39]

Progabide is a GABAderivative which acts as a dualGABA_A andGABA_B receptoragonist.^{[12][40][41][42]} It produces the morepotent GABA receptor agonistprogabide acid (SL-75102) as anactive metabolite and is additionally aprodrug ofgabamide and GABA.^{[12][41][43][42]} The drug is used as ananticonvulsant under the brand name Gabrene inFrance.^[44] The use of progabide has been limited by poor clinical effectiveness and incidence ofliver toxicity.^[45]

Picamilon (N-nicotinoyl-GABA) is aGABA analogue, specifically aconjugate of GABA andnicotinic acid (niacin), which is used as apharmaceutical drug andvasodilator inRussia for various indications.^[46][47] In addition, it has emerged insupplements elsewhere in the world and is advertised and used as a purportednootropic (cognitive enhancer).^[46][48] The drug crosses theblood–brain barrier and ishydrolyzed into GABA and nicotinic acid in animals, and hence is assumed to act as acentrally active andmetabolism-resistantprodrug of thesemetabolites.^[46][49] Picamilon itself has been found to be inactive at a large panel oftargets, including theGABA receptors,GABA transporters,GABA transaminase, andcalcium channels, which are all known targets for other GABA analogues.^[46] The drug is relatively little-researched.^[46]

Other GABA_A receptor agonists include4-AHP,^[50]dihydromuscimol,imidazole-4-acetic acid (IAA, IMA),isoguvacine,isonipecotic acid,methylglyoxal,^[51]nefiracetam (DM-9384),^[52]4-PIOL,piperidine-4-sulfonic acid (P4S),quisqualamine,^[53][54][55]thiomuscimol, andtolgabide (SL-81.0142), among others.^[56][6][57] Some of these compounds, such as isoguvacine, isonipecotic acid, and P4S, are known to be unable to cross theblood–brain barrier.^[58][7][59]

Indirectagonists of theGABA_A receptor, as well as of the otherGABA receptors, includeGABA reuptake inhibitors like theanticonvulsanttiagabine (Gabitril) andGABA transaminase (GABA-T)inhibitors like the anticonvulsantvigabatrin (Sabril).^{[60][61][62][63]}

• GABA receptor agonist
• GABA_A receptor positive allosteric modulator

• GABAA receptor agonists

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