The hypotensive effect of imidazoline ligands was attributed to both α2-adrenergic receptors and nonadrenergic imidazoline-1 receptors (I1-R). Selective I1-R ligands, devoid of the typical side effects of other centrally acting antihypertensive drugs, could be widely used in antihypertensive therapy. Thus, there is significant interest in developing new imidazoline analogs with higher selectivity and affinity for I1 receptors. The quantitative structure–activity relationship (QSAR) study of 12 ligands was carried out using multilinear regression method on I1-R and α2-adrenergic receptors binding affinities on human platelets. The compounds have been studied using Becke3LYP/3-21G (d,p) and Becke3LYP/6-31G(d,p) DFT methods. Among 42 descriptors that were considered in generating the QSAR model, three descriptors such as partial atomic charges of nitrogen in the heterocyclic moiety, distribution coefficient, and molar refractivity of the ligands resulted in a statistically significant model with R2 = 0.935 and cross-validation parameter image. The validation of the QSAR models was done by cross-validation and external test set prediction. The developed multiple linear regression models for the I1-R ligands were aimed to link the structures to their reported I1-R binding affinity log(1/Ki). The theoretical approach indicates that an increase in distribution coefficient and molar refractivity value, together with a decrease in average N-charge in the heterocyclic moiety of the ligands, causes better binding affinity for active site of the I1 receptors. The developed QSAR model is intended to predict I1-R binding affinity of related compounds and to define possible physicochemical, electronical, and structural requirements for selective I1-receptor ligands.
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