Conformational recognition by central benzodiazepine receptors

Abstract In order to distinguish conformational recognition by the receptor from steric effects brought about by substituents attached to C3 of 1,4-benzodiazepines, two series of closely related compounds were tested for binding potency. Increasing size of the 3-substituent up to isopropyl decreases both the binding and its enantioselectivity. Synthesis and X-ray determination of the molecular structure of 3,3-dimethyl derivatives possessing quasi-axial methyl substituents were followed by a mathematical separation of conformational and substituent effects for quartets with successive 3-methylation [(H) 2 , ( S )-Me, ( R )-Me, (Me) 2 at C3]. Results indicate a very high preference for conformation M of the ligand by the receptor (the primary reason of stereoselectivity) and a large steric hindrance resulting from the axial methyl substituent. A lower but still unexpectedly substantial steric effect is exerted by the equatorial methyl group.