gaboxadol

Gaboxadol acts as a GABA_A receptor agonist. It is specifically a supra-maximal agonist at α₄β₃δ, low-potency agonist at α₁β₃γ₂, partial agonist at α₄β₃γ, and antagonist at ρ1 GABA_A receptors.{{cite journal | vauthors = Brown N, Kerby J, Bonnert TP, Whiting PJ, Wafford KA | title = Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors | journal = British Journal of Pharmacology | volume = 136 | issue = 7 | pages = 965–974 | date = August 2002 | pmid = 12145096 | pmc = 1573424 | doi = 10.1038/sj.bjp.0704795 }}{{Cite journal | vauthors = Orser BA |date=2006-04-15 |title=Extrasynaptic GABAA Receptors Are Critical Targets for Sedative-Hypnotic Drugs |journal=Journal of Clinical Sleep Medicine |language=en |volume=02 |issue=2 |doi=10.5664/jcsm.26526 |issn=1550-9389|doi-access=free }}{{cite journal | vauthors = Johnston GA | title = Muscimol as an ionotropic GABA receptor agonist | journal = Neurochemical Research | volume = 39 | issue = 10 | pages = 1942–1947 | date = October 2014 | pmid = 24473816 | doi = 10.1007/s11064-014-1245-y }} Its affinity for extrasynaptic α₄β₃δ GABA_A receptors is 10-fold greater than for other subtypes.{{cite journal | vauthors = Rudolph U, Knoflach F | title = Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes | journal = Nature Reviews. Drug Discovery | volume = 10 | issue = 9 | pages = 685–697 | date = July 2011 | pmid = 21799515 | pmc = 3375401 | doi = 10.1038/nrd3502 }} 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.{{cite journal | vauthors = Mortensen M, Ebert B, Wafford K, Smart TG | title = Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors | journal = The Journal of Physiology | volume = 588 | issue = Pt 8 | pages = 1251–1268 | date = April 2010 | pmid = 20176630 | pmc = 2872731 | doi = 10.1113/jphysiol.2009.182444 }}

Compared to muscimol, gaboxadol binds less potently to α₄β₃δ GABA_A receptors ({{Abbrlink|EC₅₀|half-maximal effective concentration}} = 0.2{{nbsp}}μM vs. 13{{nbsp}}μM), but is capable of evoking a greater maximum response ({{Abbrlink|E_max|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.

Gaboxadol produced effects in clinical studies including sedation, euphoria, and dissociation or perceptual changes.{{cite journal | vauthors = Krogsgaard-Larsen P, Frølund B, Liljefors T | title = GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic | journal = Adv Pharmacol | volume = 54 | issue = | pages = 53–71 | date = 2006 | pmid = 17175810 | doi = 10.1016/s1054-3589(06)54003-7 | url = | quote = 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.}}{{cite journal | vauthors = Schoedel KA, Rosen LB, Alexander R, Wang J, Snavely D, Murphy MG, Chodakewitz J, Mengel H, Romach MK, Sellers EM | title=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 | journal=Clinical Pharmacology & Therapeutics | volume=85 | issue=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] | date=16 January 2009 | issn=0009-9236 | doi=10.1038/sj.clpt.2008.283 | pages=S9–S36 (S22–S22) | url = }} It showed less euphoria and misuse potential, more negative and dissociative effects, and fewer sedative effects than zolpidem at the assessed doses. According to Hamilton Morris, gaboxadol can produce powerful hallucinogenic effects at high doses.{{cite podcast | url=https://www.patreon.com/posts/podcast-36-with-60339541 | title=PODCAST 36: An Amanita Christmas with Dr. Povl Krogsgaard-Larsen | website=The Hamilton Morris Podcast | publisher=Patreon | host=Hamilton Morris | date=25 December 2021 | time=~48:00, ~2:07:30 | access-date=14 February 2025 | quote = [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. [...]}}{{cite podcast | url=https://www.patreon.com/posts/pod-65-dr-andrew-76525101 | title=POD 65: Dr. Andrew Gallimore on DMTx and Reality Switch Technologies | website=The Hamilton Morris Podcast | publisher=Patreon | host=Hamilton Morris | date=29 December 2022 | time=1:02:16–1:04:33 | access-date=21 March 2025 | quote = [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 [...]}}

• 4-PIOL
• Progabide

{{Reflist}}

• {{MeshName|4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol}}
• [http://www.medicalnewstoday.com/medicalnews.php?newsid=55678 Medical News Today article]
• [https://www.nytimes.com/2007/03/29/business/29sleep.html?ref=health Report of cancellation of development]

{{Hypnotics and sedatives}}

{{GABA receptor modulators}}

{{Glycine receptor modulators}}

Category:Abandoned drugs

Category:Anticonvulsants

Category:Danish inventions

Category:GABAA receptor agonists

Category:GABAA-rho receptor antagonists

Category:Glycine receptor antagonists

Category:Hypnotics

Category:Isoxazolidinones

Category:Hallucinogens

Category:Sedatives