QSAR study of imidazoline antihypertensive drugs Katarina Nikolic * , Slavica Filipic, Danica Agbaba Institute of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia article info Article history: Received 15 May 2008 Revised 19 June 2008 Accepted 26 June 2008 Available online 28 June 2008 Keywords: I 1 -receptor I 1 -R ligands Centrally acting antihypertensives Structure–activity relationship Pharmacophore abstract The hypotensive effect of imidazoline ligands was attributed to both a 2 -adrenergic receptors and nonadr- energic imidazoline-1 receptors (I 1 -R). Selective I 1 -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 I 1 receptors. The quantitative structure–activity relationship (QSAR) study of 12 ligands was carried out using multilinear regression method on I 1 -R and a 2 -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 descrip- tors 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 R 2 = 0.935 and cross-val- idation parameter q 2 pre ¼ 0:803. The validation of the QSAR models was done by cross-validation and external test set prediction. The developed multiple linear regression models for the I 1 -R ligands were aimed to link the structures to their reported I 1 -R binding affinity log(1/K i ). The theoretical approach indi- cates 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 I 1 receptors. The developed QSAR model is intended to predict I 1 -R binding affinity of related com- pounds and to define possible physicochemical, electronical, and structural requirements for selective I 1 -receptor ligands. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction The hypotensive effect of imidazoline ligands was attributed to both a 2 -adrenergic receptors (a 2 -AR) and nonadrenergic imidazo- line-1 receptors (I 1 -R). 1 Therefore, both a 2 -AR agonists and I 1 -R agonists are capable of lowering sympathetic tone by a primary action in the rostral ventrolateral medulla (RVLM). The a 2 -AR ago- nists directly inhibit presympathetic RVLM neurons. The I 1 -R ago- nists increase the release of catecholamines in the RVLM, and the catecholamines, in turn, depress presympathetic RVLM neurons by activating a 2 -AR. 2–4 According to the imidazoline hypothesis, imidazoline I 1 recep- tors in the RVLM are important for the sympathoinhibitory action of clonidine, and the role of I 1 receptors (I 1 -R) is particularly prom- inent in the case of rilmenidine and moxonidine. The antihypertensive ligands moxonidine and rilmenidine showed higher affinity for I 1 -imidazoline sites than for a 2 -AR, as well as higher selectivity for I 1 imidazoline sites than clonidine. 2–4 Rilmenidine and moxonidine cause only few a 2 -adrenoceptor- mediated side effects because they are selective for I 1 receptors. Further pharmacological studies will need to elucidate the close interdependence and interaction of these two receptors at the cel- lular level, and to explain their complex role in the central hypo- tensive effect of the ligands. Specific imidazoline receptors (I 1 -R, I 2 -R, and I 3 -R) have been characterized by extensive biochemical and physiological stud- ies. 1,5 The subcellular localization of I 1 -R to the plasma membrane has been assessed in the bovine brainstem, 6,7 in the human plate- lets, 8 and in the PC12 cells. 9,10 The I 1 -R protein structures have not yet been solved to date. Only imidazoline receptor antisera-selected (IRAS) gene candidate for the I 1 -R protein has been proposed. 11–13 Since the imidazoline binding site may only be formed when IRAS-1 is complexed to the fibronectin receptor or other partner proteins, 14 characteriza- tion of I 1 ligand–IRAS-1 complexes requires special experimental procedure. Therefore, quantitative structure–activity relationship (QSAR) study could be reliable tool for examination of the I 1 -R ligands. Previous quantum chemical studies have been restricted to sim- ilar systems (cyclic imidazolines, oxazolines, and thiazolines). 15–17 These theoretical studies set out to determine stable conforma- tions, tautomeric equilibria, gas-phase reactivity, and lipophilicity of clonidine and rilmenidine. 15 Previously determined crystal 0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2008.06.051 * Corresponding author. Tel.: +381 63 84 30 677. E-mail address: knikolic@pharmacy.bg.ac.yu (K. Nikolic). Bioorganic & Medicinal Chemistry 16 (2008) 7134–7140 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc