Development and SAR of functionally selective allosteric modulators of GABAA receptors.

摘要

Positive modulators at the benzodiazepine site of alpha2- and alpha3-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 alpha2-/alpha3-containing GABA(A) receptors and that show no functional activity at alpha1-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 alpha2- and alpha3-containing GABA(A) receptors, while simultaneously neutral antagonists at alpha1-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.