Developing dual functional allosteric modulators of GABAA receptors

Positive modulators at benzodiazepine sites of alpha 2- and alpha 3-containing GABA(A) receptors are believed to be anxiolytic. Negative allosteric modulators of alpha 5-containing GABA(A) 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 alpha 2-/alpha 3-containing GABA(A) receptors and negative modulators at alpha 5-containing GABA(A) receptors. In addition, these compounds showed no functional activity at alpha 1-containing GABA(A) receptors. Such dual functional modulators of GABA(A) receptors might be useful for treating comorbidity of anxiety and cognitive impairments in neurological and psychiatric illnesses. (C) 2010 Elsevier Ltd. All rights reserved.