Gaboxadol

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. It acts as a direct GABA_A receptor agonist. At lower doses, the drug has sedative and hypnotic effects, and at higher doses, it has hallucinogenic effects. 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.

Effects

Gaboxadol produced effects in clinical studies including sedation, euphoria, and dissociation or perceptual changes. 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. According to Hamilton Morris, gaboxadol can produce powerful hallucinogenic effects at high doses.

Pharmacology

Gaboxadol acts on the GABA system, but in a different way from other GABAergics like benzodiazepines, Z-drugs, and barbiturates. More specifically, gaboxadol acts as a direct GABA_A receptor agonist. Lundbeck states that gaboxadol also increases deep sleep (stage 4). Unlike benzodiazepines, gaboxadol does not demonstrate reinforcement in mice or baboons despite activation of dopaminergic neurons in the ventral tegmental area.

Gaboxadol is a supra-maximal agonist at α₄β₃δ, low-potency agonist at α₁β₃γ₂, partial agonist at α₄β₃γ, and antagonist at ρ1 GABA_A receptors. Its affinity for extrasynaptic α₄β₃δ GABA_A receptors is 10-fold greater than for other subtypes. Gaboxadol has a unique affinity for extrasynaptic α₄β₃δ GABA_A receptors, which mediate tonic inhibition and are typically activated by ambient, low levels of GABA in the extrasynaptic space.

Compared to muscimol, gaboxadol binds less potently to α₄β₃δ GABA_A receptors (EC₅₀Tooltip half-maximal effective concentration = 0.2μM vs. 13μM), but is capable of evoking a greater maximum response (E_maxTooltip maximal efficacy = 120% vs. 224%). The supra-maximial efficacy of gabaxadol at α₄β₃δ GABA_A receptors has been attributed to an increase in the duration and frequency of channel openings relative to the endogenous agonist GABA.

History

Gaboxadol was first synthesized in 1977 by the Danish chemist Povl Krogsgaard-Larsen. 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.

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. In March 2007, Merck and Lundbeck cancelled work on the drug, citing safety concerns and the failure of an effectiveness trial.

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. It is known internally in Ovid as OV101. By March 2023, development of gaboxadol for FXS and Angelman syndrome was discontinued. The drug is no longer under development for any indication.

See also

• GABA_A receptor § Ligands
• 4-PIOL
• Progabide

External links

• Template:Replace at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Gaboxadol - Isomer Design
• Gaboxadol - PsychonautWiki
• Merck Cancels Work on a New Insomnia Medication (2007) - The New York Times