Gaboxadol

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Gaboxadol
Clinical data
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 InfoCard100.059.039 Edit this at Wikidata
Chemical and physical data
FormulaC6H8N2O2
Molar mass140.142 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) checkY
  • Key:ZXRVKCBLGJOCEE-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Gaboxadol, also known as 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), is a conformationally constrained derivative of the alkaloid muscimol 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[edit]

Gaboxadol is a supra-maximal agonist at α4β3δ GABAA receptors, low-potency agonist at α1β3γ2, and partial agonist at α4β3γ.[5][6] Its affinity for this α4-containing subtype of the GABAA receptor is 10× greater than other non-α4 containing subtypes.[7] Gaboxadol also has a unique affinity for extrasynaptic GABAA receptors, which desensitize more slowly and less extensively than synaptic GABAA receptors.[8]

See also[edit]

References[edit]

  1. ^ a b c Morris H (August 2013). "Gaboxadol". Harper's Magazine. Retrieved 2014-11-20.
  2. ^ US 4278676, Krogsgaard-Larsen P, "Heterocyclic compounds", issued 14 July 1981, assigned to H Lundbeck AS 
  3. ^ 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): 5310–20. doi:10.1523/JNEUROSCI.4697-11.2012. PMC 6622081. PMID 22496576.
  4. ^ Tirrell M (16 April 2015). "Former Teva CEO's new gig at Ovid Therapeutics". CNBC. Retrieved 2015-05-06.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ Orser BA (April 2006). "Extrasynaptic GABAA receptors are critical targets for sedative-hypnotic drugs". Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine. 2 (2): S12–8. doi:10.5664/jcsm.26526. PMID 17557502.

External links[edit]

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