Send Orders for Reprints to reprints@benthamscience.net Letters in Drug Design & Discovery, 2014, 11, 000-000 1 1570-1808/14 $58.00+.00 ©2014 Bentham Science Publishers Correlation Between Structure, Retention and Lipophilicity of Some Anti- depressants: QSRR and QSAR Studies Danica S. Perušković, Nikola R. Stevanović * , Aleksandar D. Lolić and Rada M. Baošić * Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, Belgrade, Serbia Abstract: The objectives of this study were to gain insights into the structure-retention and structure-lipophilicity rela- tionships of series of twenty antidepressants and to propose model for estimating their retention and lipophilicity. The li- pophilicity of antidepressants has been determined by reversed-phase thin-layer chromatography using binary methanol– water mobile phases. The chemical structures of the antidepressants have been characterized by molecular descriptors which are calculated from the structure and related to the chromatographic retention parameters as well as chromatograph- ically determinated lipophilicity parameters by multiple linear regression analysis. The obtained models were used for in- terpretation of the lipophilicity and retention behavior of the investigated compounds. Keywords: Antidepressants, lipophilicity, QSAR, QSRR, reversed-phase thin layer chromatography. INTRODUCTION Quantitative structure-activity relationship (QSAR) mod- eling pertains to the construction of predictive models of biological activities as a function of structural and molecular information of compound library. Typical molecular descrip- tors used to describe electronic properties, hydrophobicity, steric effect and topology, can be determined empirically through experimentation or theoretically via computational chemistry. Computationally determined property parameters have became crucial in identifying potential drug candidates. This technique is used for the selection of the optimal candi- date for clinical investigations. Quantitative structure- retention relationship (QSRR) is useful technique that shows relationships between chromatographic properties and mole- cular descriptors characterizing the structure of investigated compounds. In this case, retention is modeled as function of structural or molecular descriptors [1-4]. Depression is a medical condition that causes a persistent feeling of sadness and loss of interest, and can cause physi- cal symptoms [5, 6]. The etiology of depression is suggested to be dysfunction of monoamine neurotransmitters in central nervous system (CNS), such as serotonin, dopamine and norepinephrine. However, the real cause of this disease is not yet known. Antidepressants are psychiatric agents used for the treatment of different types of depression [7, 8]. It is very important to control the antidepressants distribution to the place of action. The lipophilicity has a significant impact on the absorption, distribution, metabolism, and excretion of compounds (ADME properties). Antidepressants are target- ing the CNS, so they must have certain lipophilicity to be able to pass the blood brain barrier by P-glycoprotein [9, 10]. Also, the gastrointestinal resorption and distribution of drugs through the bloodstream, by means of albumin, is dependent on lipophilicity [11]. The general rule is, the more lipid *Address correspondence to these authors at the Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia; Tel: +381 11 3336 790; Fax: +381 11 2184 330; E-mails: rbaosic@chem.bg.ac.rs and nikola@chem.bg.ac.rs soluble, a molecule or drug is, the more readily it will tend to enter the brain tissue [10]. In preclinical trials the determination of lipophilicity of potential drug (through either experimental measurement or prediction) is one of the first selection criteria. The classical procedure is the determination of lipophilicity in terms of log P (the partition coefficient), which is descriptor of the diffe- rential partitioning of a neutral compound between two im- miscible solvents, usually octan-1-ol and water [12]. Instead of this method, reversed-phase thin layer chromatography (RP-TLC) is frequently used for estimation of the lipophilici- ty [13,14]. The aim of this study was to gain insights into the struc- ture-retention and structure-lipophilicity relationships of series of twenty antidepressants and to develop statistical models capable of predicting the reversed-phase chromato- graphic behavior and lipophilicity parameter based on their molecular properties. Set of the investigated compounds shows significant differences in structures. The reason for taking this diverse set of antidepressants is to determine the common structural parameter that has influence on retention and lipophilicity. MATERIALS AND METHODS Chromatography Chromatographic investigations were carried out by hori- zontal thin layer chromatography on silica gel RP18 plates, 10 × 10 cm (Merck, Darmstadt, Germany) using a Camag horizontal HPTLC development chamber in the tank confi- guration. Standard solutions (5 mg/mL) of the compounds were prepared in chloroform. The plates were spotted with 1.0 L aliquots of freshly prepared solutions of the corres- ponding compound. Before development, the spotted plates were equilibrated for 30 min in a chromatographic chamber saturated with mobile phase vapor. The used mobile phase was a mixture of methanol (as organic modifier) and water. The concentration of organic modifier in the mobile phase ranged from 50 to 80% (v/v) in 5% increments. The investi-