Exploring subtype selectivity and metabolic stability of a novel series of ligands for the benzodiazepine binding site of the GABAA receptor

A novel series of agonists at the benzodiazepine binding site of the GABAA receptor was prepared by functionalizing a known template. Adding substituents to the pyrazolone-oxygen of CGS-9896 led to a number of compounds with selectivities for either α2- or α1-containing GABAA receptor subtypes offering an entry into indications such as anxiety and insomnia. In this communication, structure–activity relationship and efforts to increase in vitro stabilities are discussed.

Graphical abstractA novel series of agonists at the benzodiazepine binding site of the GABAA receptor based on CGS-9896 was identified. SAR work and efforts to increase metabolic stabilities are described which led to the identification of potent agonists such as 19 with selectivities either for α2- or α1-containing GABAA receptors.Figure optionsDownload full-size imageDownload as PowerPoint slide