Molecular Determinants of Recognition and Activation at GABA A /Benzodiazepine Receptors MARTA FILIZOLA, DANNI L. HARRIS Molecular Research Institute, 2495 Old Middlefield Way, Mountain View, California 94043 Received 13 September 2001; accepted 16 October 2001 DOI 10.1002/qua.10110 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 GABA A /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 Wiley Periodicals, Inc. Int J Quantum Chem 88: 56–64, 2002 Key words: benzodiazepines; GABA receptors; 3D pharmacophore; multivariate discriminant analysis Correspondence to: M. Filizola; e-mail: marta@purisima. molres.org. Contract grant sponsor: NIDA. Contract grant number: DA06304. International Journal of Quantum Chemistry, Vol. 88, 56–64 (2002) © 2002 Wiley Periodicals, Inc.