3-Heteroaryl-2-pyridones: benzodiazepine site ligands with functional selectivity for alpha 2/alpha 3-subtypes of human GABA(A) receptor-ion channels
by
Collins I, Moyes C, Davey WB, Rowley M, Bromidge FA,
Quirk K, Atack JR, McKernan RM, Thompson SA, Wafford K,
Dawson GR, Pike A, Sohal B, Tsou NN, Ball RG, Castro JL.
Merck Sharp & Dohme Research Laboratories,
The Neuroscience Research Centre,
Terlings Park, Eastwick Road, Harlow,
CM20 2QR, United Kingdom.
J Med Chem. 2002 Apr 25;45(9):1887-900

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.

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