title: An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties.
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.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK. mark_chambers@merck.com
authors.forename: Mark S
authors.initials: MS
authors.lastname: Chambers
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Robert W
authors.initials: RW
authors.lastname: Carling
authors.forename: Neil
authors.initials: N
authors.lastname: Collinson
authors.forename: Susan M
authors.initials: SM
authors.lastname: Cook
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
authors.forename: Pushpindar
authors.initials: P
authors.lastname: Ferris
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Hobbs
authors.forename: Desmond
authors.initials: D
authors.lastname: O'connor
authors.forename: George
authors.initials: G
authors.lastname: Marshall
authors.forename: W
authors.initials: W
authors.lastname: Rycroft
authors.forename: Angus M
authors.initials: AM
authors.lastname: Macleod
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D003071:Cognition / Q000187:drug effects*; D004285:Dogs; D058785:GABA-A Receptor Agonists; D007555:Isoxazoles / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018697:Nootropic Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D021122:Protein Subunits; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D014227:Triazines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; C494554:MRK 016; D018697:Nootropic Agents; D021122:Protein Subunits; D011963:Receptors, GABA-A; D014227:Triazines