Study of Benzodiazepines Receptor Sites Using a Combined QSAR‐CoMFA Approach

Abstract

AbstractA quantitative structure‐activity relationship study on a set of anxiolytic benzodiazepines was carried out using the Hansch approach (QSAR) and the Comparative Molecular Field Analysis (CoMFA).The aim of the study was to investigate the nature of some of the main factors influencing the binding of the benzodiazepines to the CNS receptors. Since our preliminary QSAR results provided evidence of an involvement of a specific ligand‐receptor hydrophobic interaction, the methodological problem of how to properly include the scalar descriptor π in the development of the CoMFA model was extensively examined. The following explanatory variables were considered in the regression analyses: the HOMO and LUMO energies, the total dipole moment, the substituent constants π, ℐ, B1, B5, L, MR, the steric and the electrostatic CoMFA fields. The QSAR and the CoMFA were performed with Multilinear Regression Analysis and Partial Least Squares (PLS) Analysis, respectively. In each of the two methods the cross‐validation procedure was systematically applied to evaluate the significance of the correlation and to establish the most appropriate parametric dimensionality of the calibration models. A deeper insight into the meaning of the CoMFA electrostatic field as explanatory variable of the binding affinity was obtained by correlating the HOMO and LUMO energies with the electrostatic field itself. The results of this study suggest the existence of a specific interaction between the substituents which are in the “C7‐position”, formally corresponding to the 7‐chlorine atom in the structure of diazepam, and a receptor hydrophobic pocket. These substituents can additionally promote, through an electron‐withdrawing effect, a charge‐transfer interaction between the ligand and an electronegative receptor site.