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Gaboxadol
Chemical compound From Wikipedia, the free encyclopedia
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Gaboxadol, also known as 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), as well as by its former developmental code names LU-2-030 and OV101, is a conformationally constrained derivative of the alkaloid and Amanita muscaria constituent muscimol.[1][2] It acts as a direct GABAA receptor agonist.[1] At lower doses, the drug has sedative and hypnotic effects, and at higher doses, it has hallucinogenic effects.[1][3][2][4] Gaboxadol was studied for potential medical use as a pharmaceutical drug for a variety of indications, most notably treatment of insomnia, but was ultimately never marketed.[1][2]
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Effects
Gaboxadol produced effects in clinical studies including sedation, euphoria, and dissociation or perceptual changes.[3][5] It showed less euphoria and misuse potential, more negative and dissociative effects, and fewer sedative effects than the Z drug zolpidem at the assessed doses.[5] According to Hamilton Morris, gaboxadol can produce powerful hallucinogenic effects at high doses.[4][6]
Pharmacology
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Gaboxadol acts on the GABA system, but in a different way from other GABAergics like benzodiazepines, Z-drugs, and barbiturates.[1] More specifically, gaboxadol acts as a direct GABAA receptor agonist.[1] Lundbeck states that gaboxadol also increases deep sleep (stage 4).[1] Unlike benzodiazepines, gaboxadol does not demonstrate reinforcement in mice or baboons despite activation of dopaminergic neurons in the ventral tegmental area.[7]
Gaboxadol is a supra-maximal agonist at α4β3δ, low-potency agonist at α1β3γ2, partial agonist at α4β3γ, and antagonist at ρ1 GABAA receptors.[8][9][10] Its affinity for extrasynaptic α4β3δ GABAA receptors is 10-fold greater than for other subtypes.[11] Gaboxadol has a unique affinity for extrasynaptic α4β3δ GABAA receptors, which mediate tonic inhibition and are typically activated by ambient, low levels of GABA in the extrasynaptic space.[12]
Compared to muscimol, gaboxadol binds less potently to α4β3δ GABAA receptors (EC50 = 0.2 μM vs. 13 μM), but is capable of evoking a greater maximum response (Emax = 120% vs. 224%).[10] The supra-maximial efficacy of gabaxadol at α4β3δ GABAA receptors has been attributed to an increase in the duration and frequency of channel openings relative to the endogenous agonist GABA.[10]
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History
Gaboxadol was first synthesized in 1977 by the Danish chemist Povl Krogsgaard-Larsen.[1][2] In the early 1980s, the drug was the subject of a series of pilot studies that tested its efficacy as an analgesic and anxiolytic, as well as a treatment for tardive dyskinesia, Huntington's disease, Alzheimer's disease, and spasticity.[2]
It was not until 1996 that researchers attempted to harness gaboxadol's frequently reported sedative "adverse effect" for the treatment of insomnia, resulting in a series of clinical trials sponsored by Lundbeck and Merck.[2][1][13] In March 2007, Merck and Lundbeck cancelled work on the drug, citing safety concerns and the failure of an effectiveness trial.[14]
In 2015, Lundbeck sold its rights to the molecule to Ovid Therapeutics, whose plan is to develop it for fragile X syndrome (FXS) and Angelman syndrome.[14][15] It is known internally in Ovid as OV101.[14] By March 2023, development of gaboxadol for FXS and Angelman syndrome was discontinued.[14] The drug is no longer under development for any indication.[14]
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References
External links
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