Chiral recognition by central benzodiazepine receptors.

Abstract

1,4-Benzodiazepines in solution accommodate two chiral conformations. Two closely related quartets following the substitution pattern: 3-unsubstituted, 3S-methyl, 3R-methyl, 3,3-dimethyl, were synthesized and the binding strength of the compounds to the benzodiazepine receptor was tested. The intertwining effects of (i) conformational preference of free molecules, (ii) conformational recognition by the receptor, and (iii) axial and equatorial methyl substituents, were separated by computation. It is concluded that conformation M enriched by 3S-methyl and impoverished by 3R-methyl enantiomers is recognized by the receptor, whereas the binding is strongly and moderately hindered by axial and equatorial methyl substituents, respectively.