Selective influence on contextual memory:: Physiochemical properties associated with selectivity of benzodiazepine ligands at GABAA receptors containing the α5 subunit

Ligands that bind to the benzodiazepine binding site on the GABA(A) receptor can attenuate or potentiate cognition. To investigate this property, the chemical determinants favoring selective binding or selective activation of the alpha 5 beta 2 gamma 2 and alpha 1 beta 2 gamma 2 GABA(A) 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' terminal substituent correlated with its binding selectivity toward the alpha 5 beta 2 gamma 2 versus alpha 1 beta 2 gamma 2 isoform; while the fragment length and frontier molecular orbital energetics correlated with a compounds influence on electrophysiological activity. Compounds with promising alpha 5 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 alpha 5 beta 2 gamma 2 isoform were able to attenuate contextual memory impairment.