Gaboxadol

Last updated

Gaboxadol
Gaboxadol.svg
Clinical data
Other namesTHIP; 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol; LU-2-030; OV101; OV-101
Routes of
administration 		Oral [1]
Drug class GABAA receptor agonist; Sedative; Hypnotic; Central depressant; Hallucinogen
ATC code
  • None
Identifiers
  • 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3(2H)-one
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.059.039 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C6H8N2O2
Molar mass 140.142 g·mol−1
3D model (JSmol)
  • O=C1/C2=C(\ON1)CNCC2
  • InChI=1S/C6H8N2O2/c9-6-4-1-2-7-3-5(4)10-8-6/h7H,1-3H2,(H,8,9) Yes check.svgY
  • Key:ZXRVKCBLGJOCEE-UHFFFAOYSA-N Yes check.svgY
   (verify)

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]

Contents

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

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 Tooltip half-maximal effective concentration = 0.2 μM vs. 13 μM), but is capable of evoking a greater maximum response (Emax Tooltip maximal efficacy = 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]

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]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 Sorbera, L.A., Castaner, J., Silvestre, J.S. (2004). "Gaboxadol" . Drugs of the Future. 29 (5): 0449. doi:10.1358/dof.2004.029.05.803754 . Retrieved 19 June 2025.
  2. 1 2 3 4 5 6 Morris H (August 2013). "Gaboxadol". Harper's Magazine. Retrieved 2014-11-20.
  3. 1 2 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. PMID   17175810. 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.
  4. 1 2 Hamilton Morris (25 December 2021). "PODCAST 36: An Amanita Christmas with Dr. Povl Krogsgaard-Larsen". The Hamilton Morris Podcast (Podcast). Patreon. Event occurs at ~48:00, ~2:07:30. Retrieved 14 February 2025. [Morris:] [...] they did produce enough [gaboxadol] [...] to conduct a number of self-experiments, some at very high doses. He experienced extremely dramatic psychedelic effects at those high doses. [...] I have a written report—I mentioned that I had a friend [...] [a]nd he took a very, very large dose of [gaboxadol] [...] it was 63 mg of the zwitterion. [...] It's you know very, very dramatic hallucinogenic effects. He describes his entire reality being fragmented. [...]
  5. 1 2 Schoedel 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. ISSN   0009-9236.
  6. ↑ Hamilton Morris (29 December 2022). "POD 65: Dr. Andrew Gallimore on DMTx and Reality Switch Technologies". The Hamilton Morris Podcast (Podcast). Patreon. Event occurs at 1:02:16–1:04:33. Retrieved 21 March 2025. [Morris:] I've used high doses of gaboxadol and that is as psychedelic as anything else. It's different, of course. It's a different type of experience entirely. But that same sort of proliferation of ideas and perceptual disturbances is very much present. It is not in any way analogous to a benzodiazepine. It's something that is visionary and completely alien and strange. [...] It's worth trying. Not because it's enjoyable or good. It's also not bad either. [...] the most intense gaboxadol experience of my life was in Japan. [...] [I was like] at night I'm gonna take gaboxadol at a high dose to knock myself out. And I'd taken gaboxadol at lower doses many many times before and I'd had mild effects from it. [...] [Due to jet lag] I was much more awake and alert and unintentionally had one of the most intense psychedelic experiences of my life taking this stuff that I was thinking was just going to knock me out. [...] I spent the entire night in this visionary state trying to figure out a way to lose consciousness but instead I was hyperconscious [...]
  7. ↑ Vashchinkina E, Panhelainen A, Vekovischeva OY, Aitta-aho T, Ebert B, Ator NA, et al. (April 2012). "GABA site agonist gaboxadol induces addiction-predicting persistent changes in ventral tegmental area dopamine neurons but is not rewarding in mice or baboons". The Journal of Neuroscience. 32 (15): 5310–5320. doi: 10.1523/JNEUROSCI.4697-11.2012 . PMC   6622081 . PMID   22496576.
  8. ↑ Brown N, Kerby J, Bonnert TP, Whiting PJ, Wafford KA (August 2002). "Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors". British Journal of Pharmacology. 136 (7): 965–974. doi:10.1038/sj.bjp.0704795. PMC   1573424 . PMID   12145096.
  9. ↑ Orser BA (2006-04-15). "Extrasynaptic GABAA Receptors Are Critical Targets for Sedative-Hypnotic Drugs". Journal of Clinical Sleep Medicine. 02 (2). doi: 10.5664/jcsm.26526 . ISSN   1550-9389.
  10. 1 2 3 Johnston GA (October 2014). "Muscimol as an ionotropic GABA receptor agonist". Neurochemical Research. 39 (10): 1942–1947. doi:10.1007/s11064-014-1245-y. PMID   24473816.
  11. ↑ Rudolph U, Knoflach F (July 2011). "Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes". Nature Reviews. Drug Discovery. 10 (9): 685–697. doi:10.1038/nrd3502. PMC   3375401 . PMID   21799515.
  12. ↑ Mortensen M, Ebert B, Wafford K, Smart TG (April 2010). "Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors". The Journal of Physiology. 588 (Pt 8): 1251–1268. doi:10.1113/jphysiol.2009.182444. PMC   2872731 . PMID   20176630.
  13. ↑ US 4278676,Krogsgaard-Larsen P,"Heterocyclic compounds",issued 14 July 1981, assigned to H Lundbeck AS
  14. 1 2 3 4 5 "Gaboxadol - Lundbeck A/S". AdisInsight. 15 March 2023. Retrieved 14 February 2025.
  15. ↑ Tirrell M (16 April 2015). "Former Teva CEO's new gig at Ovid Therapeutics". CNBC. Retrieved 2015-05-06.
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