title: 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine: a functionally selective gamma-aminobutyric acid(A) (GABA(A)) alpha2/alpha3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models.
abstract: There is increasing evidence that compounds with selectivity for gamma-aminobutyric acid(A) (GABA(A)) alpha2- and/or alpha3-subtypes may retain the desirable anxiolytic activity of nonselective benzodiazepines but possess an improved side effect profile. Herein we describe a novel series of GABA(A) alpha2/alpha3 subtype-selective agonists leading to the identification of the development candidate 17, a nonsedating anxiolytic in preclinical animal assays.
authors.affiliation: Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. robert_carling@merck.com
authors.forename: Robert W
authors.initials: RW
authors.lastname: Carling
authors.forename: Andrew
authors.initials: A
authors.lastname: Madin
authors.forename: Alec
authors.initials: A
authors.lastname: Guiblin
authors.forename: Michael G N
authors.initials: MG
authors.lastname: Russell
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Moore
authors.forename: Andrew
authors.initials: A
authors.lastname: Mitchinson
authors.forename: Bindi
authors.initials: B
authors.lastname: Sohal
authors.forename: Andrew
authors.initials: A
authors.lastname: Pike
authors.forename: Susan M
authors.initials: SM
authors.lastname: Cook
authors.forename: Ian C
authors.initials: IC
authors.lastname: Ragan
authors.forename: Ruth M
authors.initials: RM
authors.lastname: McKernan
authors.forename: Kathleen
authors.initials: K
authors.lastname: Quirk
authors.forename: Pushpinder
authors.initials: P
authors.lastname: Ferris
authors.forename: George
authors.initials: G
authors.lastname: Marshall
authors.forename: Sally Ann
authors.initials: SA
authors.lastname: Thompson
authors.forename: Keith A
authors.initials: KA
authors.lastname: Wafford
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Timothy
authors.initials: T
authors.lastname: Harrison
authors.forename: José L
authors.initials: JL
authors.lastname: Castro
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Street
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D004285:Dogs; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011323:Primates; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology; D011994:Recombinant Proteins / Q000819:agonists; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014981:Xenopus
chemical_list: C507018:7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo(4,3-b)pyridazine; D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; C546240:GABRA1 protein, human; C484841:GABRA2 protein, human; C546257:GABRA3 protein, human; C546241:Gabra1 protein, mouse; C546258:Gabra3 protein, mouse; D006993:Hypnotics and Sedatives; D011724:Pyridazines; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D014230:Triazoles