Molecular determinants of recognition and activation at GABAA/benzodiazepine receptors

Abstract

Benzodiazepines (BDZ) are among the most widely prescribed drugs known to date. However, their broad spectrum of behavioral activity and lack of specificity circumscribe their effectiveness as drugs. With the goal of designing more selective benzodiazepine receptor ligands, Dr. Loew's research group has contributed to literature over the years with both experimental and computational studies. We report here a summary of the most recent computational work carried out in our laboratory on 21 structurally diverse benzodiazepine receptor ligands, using as a data set their in-house experimental results of activity at the anxiolytic, sedative, and hyperphagic endpoints. The chemical and geometric determinants common to the overlapping binding regions of benzodiazepine agonists, antagonists, and inverse agonists were identified at each of these three behavioral endpoints. The three resulting 3D pharmacophores did not encompass all the molecular requirements for recognition and activation of GABAA/BDZ receptors. They provided instead a means of obtaining accurate bioactive conformations for use in statistical studies, such as quantitative structure-activity relationship and multivariate discriminant analyses. These studies can serve as a guide to predict both ligand affinities and activities. In the present work, multivariate discriminant analysis of global physicochemical properties is performed to provide new hypotheses for activation selectivity at the sedation endpoint. Although this analysis relies on a relatively small set of compounds, its results can still aim at compound screening and future identification of novel selective benzodiazepine receptor ligands. © 2002 John Wiley & Sons, Inc. Int J Quantum Chem, 2002