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.

A 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 as PowerPoint slide