Chemistry:Gaboxadol

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Short description: Chemical compound
Gaboxadol
Gaboxadol.svg
Clinical data
ATC code
  • none
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC6H8N2O2
Molar mass140.142 g·mol−1
3D model (JSmol)
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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

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

References

  1. ↑ 1.0 1.1 1.2 Morris, Hamilton (August 2013). "Gaboxadol". Harper's Magazine August 2013. http://harpers.org/archive/2013/08/gaboxadol/. Retrieved 2014-11-20. 
  2. ↑ US Patent 4278676 - Heterocyclic compounds
  3. ↑ "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. April 2012. doi:10.1523/JNEUROSCI.4697-11.2012. PMID 22496576. 
  4. ↑ Tirrell, Meg (16 April 2015). "Former Teva CEO's new gig at Ovid Therapeutics". CNBC. https://www.cnbc.com/id/102591288. 
  5. ↑ Brown, N.; Kerby, J.; Bonnert, T. P.; Whiting, P. J.; Wafford, K. A. (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. ISSN 0007-1188. PMID 12145096. 
  6. ↑ Orser, Beverley A. (2006-04-15). "Extrasynaptic GABAA Receptors Are Critical Targets for Sedative-Hypnotic Drugs" (in en). Journal of Clinical Sleep Medicine 02 (2). doi:10.5664/jcsm.26526. ISSN 1550-9389. 
  7. ↑ Rudolph, Uwe; Knoflach, Frédéric (2011-07-29). "Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes". Nature Reviews. Drug Discovery 10 (9): 685–697. doi:10.1038/nrd3502. ISSN 1474-1776. PMID 21799515. 
  8. ↑ Orser, Beverley A. (2006-04-15). "Extrasynaptic GABAA Receptors Are Critical Targets for Sedative-Hypnotic Drugs" (in en). Journal of Clinical Sleep Medicine 02 (2). doi:10.5664/jcsm.26526. ISSN 1550-9389. 

External links

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See also
Receptor/signaling modulators
GABAA receptor positive modulators
GABA metabolism/transport modulators

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