3-Heteroaryl-2-pyridones:  Benzodiazepine Site Ligands with Functional Selectivity for α2/α3-Subtypes of Human GABAA Receptor-Ion Channels

• Published in: Journal of medicinal chemistry Vol. 45; no. 9; pp. 1887 - 1900
• Main Authors: Collins, Ian, Moyes, Christopher, Davey, William B, Rowley, Michael, Bromidge, Frances A, Quirk, Kathleen, Atack, John R, McKernan, Ruth M, Thompson, Sally-Ann, Wafford, Keith, Dawson, Gerard R, Pike, Andrew, Sohal, Bindi, Tsou, Nancy N, Ball, Richard G, Castro, José L
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 25-04-2002
• Subjects: Biological and medical sciences; Gabaergic and benzodiazepinic system; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Partial agonist; Five membered ring; Rat; Nitrogen heterocycle; Ligand; Thiazole derivatives; Lactam; Anticonvulsant; Selectivity; Ester; Structure activity relation; Chemical synthesis; Human; Sulfur nitrogen heterocycle; Rodentia; Oral administration; Bioavailability; In vitro; In vivo; Vertebrata; Biological fixation; Mammalia; Tranquillizer; Mouse; Animal; Affinity; Pharmacokinetics; Gabaergic receptor A; Subtype
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0110789

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 γ-aminobutyric acid (GABAA) receptor ion channels, low binding selectivity for α2- and/or α3- over α1-containing GABAA receptor subtypes and high binding selectivity over α5 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 α2 and/or α3 GABAA receptor subtypes over α1 was observed in several of these compounds in electrophysiological assays. Furthermore, an α3 subtype selective inverse agonist was proconvulsant and anxiogenic in rodents while an α2/α3 subtype selective partial agonist was anticonvulsant and anxiolytic, supporting the hypothesis that subtype selective BZ site agonists may provide new anxiolytic therapies.