Selective Influence on Contextual Memory: Physiochemical Properties Associated with Selectivity of Benzodiazepine Ligands at GABAA Receptors Containing the a5 Subunit.

[摘要]：Ligands that bind to the benzodiazepine binding site on the GABAA receptor can attenuate or potentiate cognition. To investigate this property, the chem. determinants favoring selective binding or selective activation of the a5b2g2 and a1b2g2 GABAA receptor isoforms were examd. A 3D-pharmacophore, developed from a diverse set of BDZR ligands, was used as an initial basis for multivariate discriminant, fragment, and 3D-quant. structure-activity relation analyses, which formed the criteria for selection of addnl. compds. for study. We found that the electrostatic potential near the ligands' terminal substituent correlated with its binding selectivity toward the a5b2g2 vs. a1b2g2 isoform; while the fragment length and frontier MO energetics correlated with a compds. influence on electrophysiol. activity. Compds. with promising a5 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 a5b2g2 isoform were able to attenuate contextual memory impairment.

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