title: Tricyclic pyridones as functionally selective human GABAA alpha 2/3 receptor-ion channel ligands.
abstract: A series of tricyclic pyridones has been evaluated as benzodiazepine site ligands with functional selectivity for the alpha(3) over the alpha(1) containing subtype of the human GABA(A) receptor ion channel. This investigation led to the identification of a high affinity, functionally selective, orally bioavailable benzodiazepine site ligand that demonstrated activity in rodent anxiolysis models and reduced sedation relative to diazepam.
authors.affiliation: Department of Medicinal Chemistry, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. james_crawforth@merck.com
authors.forename: James
authors.initials: J
authors.lastname: Crawforth
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Susan M
authors.initials: SM
authors.lastname: Cook
authors.forename: Karl R
authors.initials: KR
authors.lastname: Gibson
authors.forename: Alan
authors.initials: A
authors.lastname: Nadin
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Owens
authors.forename: Andrew
authors.initials: A
authors.lastname: Pike
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Bindi
authors.initials: B
authors.lastname: Sohal
authors.forename: Francine
authors.initials: F
authors.lastname: Sternfeld
authors.forename: Keith
authors.initials: K
authors.lastname: Wafford
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Street
mesh_terms: D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008024:Ligands; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism*; D011728:Pyridones / Q000737:chemistry* / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: C484841:GABRA2 protein, human; D008024:Ligands; D021122:Protein Subunits; D011728:Pyridones; D011963:Receptors, GABA-A