An Updated Unified Pharmacophore Model of the Benzodiazepine Binding Site on γ-Aminobutyric Acida Receptors: Correlation with Comparative Models
T. Clayton, J. L. Chen, M. Ernst, L. Richter, B. A. Cromer, C. J. Morton, H. Ng, C. C. Kaczorowski, F. J. Helmstetter, R. Furtmuller, G. Ecker, M. W. Parker, W. Sieghart and J. M. Cook
Affiliation: Department of Chemistry, 3210 North Cramer Street, UW-Milwaukee, Chemistry Building Milwaukee, WI 53201, UWMilwaukee,Milwaukee, WI 53211, USA.
A successful unified pharmacophore/receptor model which has guided the synthesis of subtype selective compounds is reviewed in light of recent developments both in ligand synthesis and structural studies of the binding site itself. The evaluation of experimental data in combination with a comparative model of the α1β2γ2 GABAA receptor leads to an orientation of the pharmacophore model within the Bz BS. Results not only are important for the rational design of selective ligands, but also for the identification and evaluation of possible roles which specific residues may have within the benzodiazepine binding pocket.
Keywords: Aminobutyric acid(A) receptors, gated ion channels, GABA-A, computer-assisted analysis, benzodiazepine
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