title: 3-Heteroaryl-2-pyridones: benzodiazepine site ligands with functional delectivity for alpha 2/alpha 3-subtypes of human GABA(A) receptor-ion channels.
abstract: A novel series of 3-heteroaryl-5,6-bis(aryl)-1-methyl-2-pyridones were developed with high affinity for the benzodiazepine (BZ) binding site of human gamma-aminobutyric acid (GABA(A)) receptor ion channels, low binding selectivity for alpha 2- and/or alpha 3- over alpha 1-containing GABA(A) receptor subtypes and high binding selectivity over alpha 5 subtypes. High affinity appeared to be associated with a coplanar conformation of the pyridone and sulfur-containing 3-heteroaryl rings resulting from an attractive S.O intramolecular interaction. Functional selectivity (i.e., selective efficacy) for alpha 2 and/or alpha 3 GABA(A) receptor subtypes over alpha1 was observed in several of these compounds in electrophysiological assays. Furthermore, an alpha 3 subtype selective inverse agonist was proconvulsant and anxiogenic in rodents while an alpha 2/alpha 3 subtype selective partial agonist was anticonvulsant and anxiolytic, supporting the hypothesis that subtype selective BZ site agonists may provide new anxiolytic therapies.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, CM20 2QR, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
authors.forename: Christopher
authors.initials: C
authors.lastname: Moyes
authors.forename: William B
authors.initials: WB
authors.lastname: Davey
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Frances A
authors.initials: FA
authors.lastname: Bromidge
authors.forename: Kathleen
authors.initials: K
authors.lastname: Quirk
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Ruth M
authors.initials: RM
authors.lastname: McKernan
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Thompson
authors.forename: Keith
authors.initials: K
authors.lastname: Wafford
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
authors.forename: Andrew
authors.initials: A
authors.lastname: Pike
authors.forename: Bindi
authors.initials: B
authors.lastname: Sohal
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Tsou
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ball
authors.forename: José L
authors.initials: JL
authors.lastname: Castro
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003292:Convulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004827:Epilepsy / Q000188:drug therapy; D018755:GABA Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009865:Oocytes; D018408:Patch-Clamp Techniques; D021122:Protein Subunits; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D003292:Convulsants; D018755:GABA Agonists; D008024:Ligands; D021122:Protein Subunits; D011728:Pyridones; D011963:Receptors, GABA-A