QSAR study of selective I1-imidazoline receptor ligands

Selective imidazoline(1)-receptor (I(1)-R) ligands are used clinically to reduce blood pressure. Thus, there is significant interest in developing new imidazoline analogs with high selectivity and affinity for I(1) receptors. A quantitative structure-activity relationship (QSAR) study was carried out on 11 potent I(1)-R ligands (derivatives of imidazoline, oxazoline and pyrroline) using a multiple linear regression (MLR) procedure. The selected compounds have been studied using B3LYP/3-21G(d, p) and B3LYP/6-31G(d, p) methods. Among the 42 descriptors that were considered in generating the QSAR model, three descriptors (partial atomic charges of nitrogen in the heterocyclic moiety (N-2 charge), log D and the dipole moment of the ligands) resulted in a statistically significant model with r(2) > 0.874 and [image omitted] > 0.802. The QSAR models were validated through cross-validation and external test set prediction. The aim of the developed MLR models for the I(1)-R ligands was to link the structures to their reported I(1)-R binding affinity log(1/Ki). The proposed QSAR models indicate that an increase in log D and the dipole moment value and a decrease in N-2 charge in the heterocyclic moiety are predictors of better selectivity and affinity for I(1) receptors. The developed QSAR model is intended to predict the I(1)-R binding affinity of related compounds and aid in the rational design of new potent and selective I(1)-R ligands.