Properties of selective type I benzodiazepine receptor ligands

Abstract

Conformational studies on zolpidem, and ICI 190,622, three type I selective benzodiazepine receptor ligands, are presented. The semiempirical quantum mechanical AM 1 technique was used, and all possible torsions were rotated systematically in 30" increments. In addition, each of the structures was subjected to molecular dynamics simulation at 3 10 K, to study their conformational flexibility at physiologically relevant temperatures. Zolpidem and 2-oxoquazepam have two low-energy conformers each that can not interconvert. By contrast, ICI 190,622 has several low-energy equilibrium structures, each of which could be accessed from any other minimum in the simulation. For each of these three selective analogs, for CL 2 18,872, and for the nonselective diazepam, flunitrazepam, and triazolam, steric and electronic properties were calculated and examined for their role as determinants of type 1 receptor recognition and selectivity. Specifically, the "sterimol" parameters, which provide quantitative measures of the shape, and heats of protonation for each analog were calculated. The geometric parameter that describes the maximum separation between any two points on the molecular surface appears to be a good discriminant of selectivity.