3-heteroaryl-2-pyridones:: Benzodiazepine site ligands with functional selectivity for α2/α3-subtypes of human GABAA receptor-ion channels

被引：113

作者：

Collins, I ^{[1
]}

Moyes, C ^{[1
]}

Davey, WB ^{[1
]}

Rowley, M ^{[1
]}

Bromidge, FA ^{[1
]}

Quirk, K ^{[1
]}

Atack, JR ^{[1
]}

McKernan, RM ^{[1
]}

Thompson, SA ^{[1
]}

Wafford, K ^{[1
]}

Dawson, GR ^{[1
]}

Pike, A ^{[1
]}

Sohal, B ^{[1
]}

Tsou, NN ^{[1
]}

Ball, RG ^{[1
]}

Castro, JL ^{[1
]}

机构：

[1] Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Harlow CM20 2QR, Essex, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2002年 / 45卷 / 09期

关键词：

D O I：

10.1021/jm0110789

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 alpha2- and/or alpha3- over alpha1-containing GABA(A) receptor subtypes and high binding selectivity over alpha5 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 alpha2 and/or alpha3 GABA(A) receptor subtypes over alpha1 was observed in several of these compounds in electrophysiological assays. Furthermore, an alpha3 subtype selective inverse agonist was proconvulsant and anxiogenic in rodents while an alpha2/alpha3 subtype selective partial agonist was anticonvulsant and anxiolytic, supporting the hypothesis that subtype selective BZ site agonists may provide new anxiolytic therapies.

引用

页码：1887 / 1900

页数：14

共 55 条

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