Development and SAR of functionally selective allosteric modulators of GABAA receptors

Positive modulators at the benzodiazepine site of α2- and α3-containing GABA A receptors are believed to be anxiolytic. Through oocyte voltage clamp studies, we have discovered two series of compounds that are positive modulators at α2-/α3-containing GABA A receptors and that show no functional activity at α1-containing GABA A receptors. We report studies to improve this functional selectivity and ultimately deliver clinical candidates. The functional SAR of cinnolines and quinolines that are positive allosteric modulators of the α2- and α3-containing GABA A receptors, while simultaneously neutral antagonists at α1-containing GABA A receptors, is described. Such functionally selective modulators of GABA A receptors are expected to be useful in the treatment of anxiety and other psychiatric illnesses.