Selective influence on contextual memory: Physiochemical properties associated with selectivity of benzodiazepine ligands at GABA\u3csub\u3eA\u3c/sub\u3e receptors containing the α5 subunit

Ligands that bind to the benzodiazepine binding site on the GABA receptor can attenuate or potentiate cognition. To investigate this property, the chemical determinants favoring selective binding or selective activation of the α5β2γ2 and α1β2γ2 GABA receptor isoforms were examined. A 3D-pharmacophore, developed from a diverse set of BDZR ligands, was used as an initial basis for multivariate discriminant, fragment, and 3D-quantitative structure-activity relationship analyses, which formed the criteria for selection of additional compounds for study. We found that the electrostatic potential near the ligands\u27 terminal substituent correlated with its binding selectivity toward the α5β2γ2 versus α1β2γ2 isoform; while the fragment length and frontier molecular orbital energetics correlated with a compounds influence on electrophysiological activity. Compounds with promising α5 profiles were further assessed for their ability to attenuate scopolamine-induced contextual memory impairment in mice. Surprisingly, both weak inverse agonist and antagonists that display binding selectivity toward the α5β2γ2 isoform were able to attenuate contextual memory impairment. © 2008 American Chemical Society. A