6,7-Dihydro-2-benzothiophen-4(5H)-ones: A novel class of GABA-A α5 receptor inverse agonists

Nonselective inverse agonists at the benzodiazepine binding site on the GABA-A chloride ion channel enhance cognitive performance in animals but cannot be used in the treatment of cognitive disorders because of anxiogenic and convulsant side effects. We have identified a novel series of GABA-A α5 receptor ligands during our search for α5 receptor inverse agonists as potential cognition enhancers. In particular, 6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-di-hydro-2-benzothiophen-4(5H)-one (26) has been identified as a functionally selective GABA-A a5 inverse agonist.