An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties

  • J Med Chem. 2004 Nov 18;47(24):5829-32. doi: 10.1021/jm040863t.
Mark S Chambers  1 ,  John R Atack ,  Robert W Carling ,  Neil Collinson ,  Susan M Cook ,  Gerard R Dawson ,  Pushpindar Ferris ,  Sarah C Hobbs ,  Desmond O'connor ,  George Marshall ,  W Rycroft ,  Angus M Macleod
Affiliations
  • 1. Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK. [email protected]
PMID: 15537339 DOI: 10.1021/jm040863t
Abstract

(3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine (13) has been identified as a functionally selective, inverse agonist at the benzodiazepine site of GABA(A) alpha5 receptors. 13 is orally bioavailable, readily penetrates the CNS, and enhances performance in animal models of cognition. It does not exhibit the convulsant, proconvulsant, or anxiogenic activity associated with nonselective GABA(A) inverse agonists.

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