title: 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.
abstract: 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.
authors.affiliation: Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. simon.goodacre@merck.com
authors.forename: Simon C
authors.initials: SC
authors.lastname: Goodacre
authors.forename: David J
authors.initials: DJ
authors.lastname: Hallett
authors.forename: Robert W
authors.initials: RW
authors.lastname: Carling
authors.forename: José L
authors.initials: JL
authors.lastname: Castro
authors.forename: David S
authors.initials: DS
authors.lastname: Reynolds
authors.forename: Andrew
authors.initials: A
authors.lastname: Pike
authors.forename: Keith A
authors.initials: KA
authors.lastname: Wafford
authors.forename: Robert
authors.initials: R
authors.lastname: Newman
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Street
mesh_terms: 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
chemical_list: 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