Imidazo[1,2-a]pyrazin-8-ones, imidazo[1,2-d][1,2,4]triazin-8-ones and imidazo[2,1-f][1,2,4]triazin-8-ones as alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety.
Imidazo[1,2-a]pyrazin-8-ones, imidazo[1,2-d][1,2,4]triazin-8-ones and imidazo[2,1-f][1,2,4]triazin-8-ones are high affinity GABA(A) agonists. Compound 16d has good oral bioavailability in rat, functional selectivity for the GABA(A)alpha2 and alpha3-subtypes and is anxiolytic in a conditioned animal model of anxiety with minimal sedation observed at full BZ binding site occupancy.
Goodacre
Simon C
SC
Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. simon.goodacre@merck.com
Hallett
David J
DJ
Carling
Robert W
RW
Castro
José L
JL
Reynolds
David S
DS
Pike
Andrew
A
Wafford
Keith A
KA
Newman
Robert
R
Atack
John R
JR
Street
Leslie J
LJ
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001008:Anxiety Disorders / Q000188:drug therapy*; D001569:Benzodiazepines / Q000378:metabolism; D001665:Binding Sites; D001682:Biological Availability; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D018755:GABA Agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D051381:Rats; D011963:Receptors, GABA-A; D011994:Recombinant Proteins / Q000819:agonists; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; C484841:GABRA2 protein, human; C546257:GABRA3 protein, human; C546258:Gabra3 protein, mouse; C546259:Gabra3 protein, rat; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D001569:Benzodiazepines