An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties.
(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.
Chambers
Mark S
MS
Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK. mark_chambers@merck.com
Atack
John R
JR
Carling
Robert W
RW
Collinson
Neil
N
Cook
Susan M
SM
Dawson
Gerard R
GR
Ferris
Pushpindar
P
Hobbs
Sarah C
SC
O'connor
Desmond
D
Marshall
George
G
Rycroft
W
W
Macleod
Angus M
AM
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
D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; C494554:MRK 016; D018697:Nootropic Agents; D021122:Protein Subunits; D011963:Receptors, GABA-A; D014227:Triazines