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Stereochemical features controlling binding and intrinsic activity properties of benzodiazepine-receptor ligands

PA Borea, G Gilli, V Bertolasi and V Ferretti

Benzodiazepine-receptor ligands belong to several different chemical classes. All of them bind to the receptor but display a variety of biological effects ranging from agonist to inverse agonist to antagonist. The properties of the most representative compounds for each class are briefly reviewed as concerns their receptor binding affinities, gamma-aminobutyric acid ratios, photoaffinity labeling ratios, and pharmacological properties. Their geometries, as obtained by X-ray crystallography, are discussed and missing crystal and molecular structures of two of them (zopiclone and CL 218-872) are reported. Binding and intrinsic activity properties of series of benzodiazepines and beta-carbolines are extensively analyzed and correlated with their molecular structures. A general stereochemical model accounting for both binding abilities and kinds of biochemical and pharmacological activities for all benzodiazepine-receptor ligands is proposed. This is based on the assumption of a rather diffuse and substantially planar recognition site where the main drug-receptor interactions are mediated by the drug carbonylic or iminic groups via hydrogen bonding and the observed differences in pharmacological profiles are accounted for by the different localization of the different ligands inside this unique binding site.

Volume 31, Issue 4, pp. 334-344, 04/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1987 by the American Society for Pharmacology and Experimental Therapeutics