GABAA receptor agonist

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Not to be confused with GABAA receptor positive allosteric modulator.
GABAA receptor agonist
Drug class
Gaboxadol (THIP), a well-known GABAA receptor agonist and hypnotic.
Class identifiers
SynonymsGABAA agonist
UseSeizures, insomnia, hallucinogenic effects
Mechanism of actionGABAA receptor agonism
Biological targetGABAA receptor
Chemical classGABA analogues and others
Legal status

A GABAA receptor agonist is a drug that acts as an orthosteric agonist of the GABAA receptor, the major signaling receptor of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).[1][2][3]

The mechanism of action of GABAA receptor agonists is unlike that of GABAA positive allosteric modulators, including benzodiazepines, Z drugs, barbiturates, neurosteroids, and alcohol, which instead act via allosteric regulatory sites to potentiate GABAA receptor function.[4][3] GABAA receptor agonists have different effects from those of GABAA receptor positive allosteric modulators.[5][6][7][8]

Examples of GABAA receptor agonists include GABA itself, γ-amino-β-hydroxybutyric acid (GABOB), muscimol (found in Amanita muscaria mushrooms), gaboxadol (THIP), and progabide, among others.[1][2][3] High-efficacy GABAA receptor agonists have been found to produce sedative, hypnotic, anticonvulsant, and hallucinogenic effects, among others.[9][10][11][12] The structural requirements for GABAA receptor binding and activation have been found to be very strict, so relatively few high-efficacy GABAA receptor agonists are known.[2][13] No fully selective GABAA receptor agonists, for instance lacking any additional activity at the closely related GABAA-ρ and/or GABAB receptors, are currently known.[14]

GABAA receptor agonists are generally GABA analogues and derivatives.[1][2] Muscimol, a conformationally restrained analogue of GABA, was among the first GABAA receptor agonists to be identified.[15]

GABA

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Main article: γ-Aminobutyric acid
Chemical structure of γ-aminobutyric acid (GABA).

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system.[6][16][17] It is present in about 25 to 50% of neurons in the brain.[17] The neurotransmitter acts as a non-selective agonist of all three types of GABA receptors, including the GABAA receptor, GABAB receptor, and GABAA-rho receptor (GABAC receptor).[6][16] GABA is available as an over-the-counter supplement and is often taken for self-treatment of insomnia and anxiety.[18][19] However, GABA is highly susceptible to metabolism, has a very short elimination half-life, and is unable to cross the blood–brain barrier.[18][19] As such, the therapeutic benefits of exogenous GABA are questionable.[19]

GABOB

[edit]
Main article: γ-Amino-β-hydroxybutyric acid
Chemical structure of γ-amino-β-hydroxybutyric acid (GABOB; Gamibetal).

γ-Amino-β-hydroxybutyric acid (GABOB) is a close endogenous analogue of GABA found in the human brain.[20] It acts as a dual GABAA and GABAB receptor agonist.[21] The drug has anticonvulsant effects and has been used in the treatment of epilepsy under brand names like Gamibetal in some countries throughout the world.[22][20][23]

Muscimol

[edit]
Main article: Muscimol
Chemical structure of muscimol, found in Amanita muscaria.
Amanita muscaria (fly agaric) mushrooms, which contain muscimol.

Muscimol is an alkaloid found in Amanita mushrooms such as Amanita muscaria (fly agaric).[10][15][24] It is a conformationally constrained derivative of GABA.[15][25] The drug is a highly potent GABAA receptor full agonist.[10][15] However, it is a selective or preferential agonist of extrasynaptic δ subunit-containing GABAA receptors.[10][26][27] The drug also acts as a potent GABAA-ρ receptor partial agonist and weak GABA reuptake inhibitor.[10][15][25] Muscimol is a sedative and hallucinogen.[10][28][29] Ibotenic acid, another alkaloid found in Amanita mushrooms, is a neurotoxin but functions as a prodrug of muscimol and has similar effects.[30][28][25] Muscimol has served as the base structure for development of many synthetic GABA system modulators, including GABA receptor modulators and GABA reuptake inhibitors.[5][31] The compound has been used recreationally as a hallucinogen and has become increasingly used at low doses for claimed therapeutic benefits, such as sleep improvement.[10][32][33][34]

Gaboxadol

[edit]
Main article: Gaboxadol
Chemical structure of gaboxadol (THIP).

Gaboxadol (THIP) is a synthetic derivative of muscimol which acts as a potent GABAA receptor partial agonist.[7][8][11] However, it is a selective or preferential supramaximal agonist of extrasynaptic δ subunit-containing GABAA receptors.[2][7][9] The drug is also a potent GABAA-ρ receptor antagonist.[14] Gaboxadol has improved selectivy and drug-like properties compared to muscimol.[7][15][5][11] It has sedative, hypnotic, and, at high doses, hallucinogenic effects.[8][2][11] The drug was developed for treatment of insomnia 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 increased slow wave sleep (deep sleep).[8][2][35] Gaboxadol completed phase 3 clinical trials for this indication.[36] However, it was discontinued for various reasons, most notably a narrow therapeutic index with high rates of hallucinogenic effects at supratherapeutic doses.[37][38][39]

Progabide

[edit]
Main article: Progabide
Chemical structure of progabide (Gabrene).

Progabide is a GABA derivative which acts as a dual GABAA and GABAB receptor agonist.[12][40][41][42] It produces the more potent GABA receptor agonist progabide acid (SL-75102) as an active metabolite and is additionally a prodrug of gabamide and GABA.[12][41][43][42] The drug is used as an anticonvulsant under the brand name Gabrene in France.[44] The use of progabide has been limited by poor clinical effectiveness and incidence of liver toxicity.[45]

Picamilon

[edit]
Main article: Picamilon
Chemical structure of picamilon (N-nicotinoyl-GABA).

Picamilon (N-nicotinoyl-GABA) is a GABA analogue, specifically a conjugate of GABA and nicotinic acid (niacin), which is used as a pharmaceutical drug and vasodilator in Russia for various indications.[46][47] In addition, it has emerged in supplements elsewhere in the world and is advertised and used as a purported nootropic (cognitive enhancer).[46][48] The drug crosses the blood–brain barrier and is hydrolyzed into GABA and nicotinic acid in animals, and hence is assumed to act as a centrally active and metabolism-resistant prodrug of these metabolites.[46][49] Picamilon itself has been found to be inactive at a large panel of targets, including the GABA receptors, GABA transporters, GABA transaminase, and calcium channels, which are all known targets for other GABA analogues.[46] The drug is relatively little-researched.[46]

Others

[edit]

Other GABAA receptor agonists include 4-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, and tolgabide (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 the blood–brain barrier.[58][7][59]

Indirect agonists

[edit]
Main articles: GABA reuptake inhibitor and GABA transaminase inhibitor

Indirect agonists of the GABAA receptor, as well as of the other GABA receptors, include GABA reuptake inhibitors like the anticonvulsant tiagabine (Gabitril) and GABA transaminase (GABA-T) inhibitors like the anticonvulsant vigabatrin (Sabril).[60][61][62][63]

See also

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References

[edit]
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