Gaboxadol, also known as 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), is a conformationally constrained derivative of the alkaloidmuscimol that was first synthesized in 1977 by the Danish chemist Poul Krogsgaard-Larsen.[1] In the early 1980s gaboxadol 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.[1] 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.[1][2] In March, 2007, Merck and Lundbeck cancelled work on the drug, citing safety concerns and the failure of an efficacy trial. It acts on the GABA system, but in a different way from benzodiazepines, Z-Drugs, and barbiturates. 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.[3]
In 2015, Lundbeck sold its rights to the molecule to Ovid Therapeutics, whose plan is to develop it for FXS and Angelman syndrome.[4] It is known internally in Ovid as OV101.
Pharmacology
Gaboxadol is a supra-maximal agonist at α4β3δ, low-potency agonist at α1β3γ2, partial agonist at α4β3γ, and antagonist at ρ1GABAA receptors.[5][6][7] Its affinity for extrasynaptic α4β3δ GABAA receptors is 10-fold greater than other subtypes.[8] 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.[9]
Compared to muscimol, gaboxadol binds less potently to α4β3δ GABAA receptors (EC50 .2μM vs 13μM), but is capable of evoking a greater maximum response (Emax 120% vs 224%).[7] 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.[7]
^Krogsgaard-Larsen P, Frølund B, Liljefors T (2006). "GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic". Adv Pharmacol. 54: 53–71. doi:10.1016/s1054-3589(06)54003-7. PMID17175810. In cancer patients and also in patients with chronic anxiety (Hoehn‐Saric, 1983) the desired effects of Gaboxadol were accompanied by side effects, notably sedation, nausea, and in a few cases euphoria. The side effects of Gaboxadol have, however, been described as mild and similar in quality to those of other GABA‐mimetics (Hoehn‐Saric, 1983). This combination of analgesic and anxiolytic effects of THIP obviously has therapeutic prospects.
^ abSchoedel KA, Rosen LB, Alexander R, Wang J, Snavely D, Murphy MG, et al. (16 January 2009). "Poster Session I (PI 1-89): PI-44: A single-dose randomized, double-blind, crossover abuse liability study to evaluate the subjective and objective effects of gaboxadol and zolpidem in recreational drug users". Clinical Pharmacology & Therapeutics. 85 (S1 [Supplement: Abstracts of the 2009 Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics. National Harbor, Maryland, USA. March 18‐21, 2009]): S9–S36 (S22–S22). doi:10.1038/sj.clpt.2008.283. ISSN0009-9236.
