Developing dual functional allosteric modulators of GABAA receptors

Abstract

Positive modulators at benzodiazepine sites of α2- and α3-containing GABAA receptors are believed to be anxiolytic. Negative allosteric modulators of α5-containing GABAA receptors enhance cognition. By oocyte two-electrode voltage clamp and subsequent structure–activity relationship studies, we discovered cinnoline and quinoline derivatives that were both positive modulators at α2-/α3-containing GABAA receptors and negative modulators at α5-containing GABAA receptors. In addition, these compounds showed no functional activity at α1-containing GABAA receptors. Such dual functional modulators of GABAA receptors might be useful for treating comorbidity of anxiety and cognitive impairments in neurological and psychiatric illnesses.