Abstract
A quantitative structure-activity relationship (QSAR) study has been made on 20 compounds with serotonin (5-HT) receptor affinity. Thin-layer chromatographic (TLC) data and physicochemical parameters were applied in this study. RP2 TLC 60F254 plates (silanized) impregnated with solutions of propionic acid, ethylbenzene, 4-ethylphenol, and propionamide (used as analogues of the key receptor amino acids) and their mixtures (denoted as S1–S7 biochromatographic models) were used in two developing phases as a model of drug-5-HT receptor interaction. The semiempirical method AM1 (HyperChem v. 7.0 program) and ACD/Labs v. 8.0 program were employed to calculate a set of physicochemical parameters for the investigated compounds. Correlation and multiple linear regression analysis were used to search for the best QSAR equations. The correlations obtained for the compounds studied represent their interactions with the proposed biochromatographic models. The good multivariate relationships (R 2 = 0.78–0.84) obtained by means of regression analysis can be used for predicting the quantitative effect of biological activity of different compounds with 5-HT receptor affinity. “Leave-one-out” (LOO) and “leave-N-out” (LNO) cross-validation methods were used to judge the predictive power of final regression equations.
Highlights
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter in the central nervous system (CNS) that plays a significant role in migraine attacks, mood regulation, sleep, appetite, sexual function, anxiety treatment, depression, and schizophrenia
The present work is a continuation of the previous studies [13, 14], whose purpose is to determine the possibility of using data obtained from thin-layer chromatography and computer-calculated physicochemical parameters to build regression equations that will predict the receptor binding affinity and agonist and antagonistic activity of selected compounds acting on serotoninergic receptors
On the basis of the information, was established that the following amino acids: aspartic acid (Asp155), serine (Ser159), phenylalanine (Phe340), asparagine (Asn333), tyrosine (Tyr370), threonine (Thr196), and tryptophan (Trp200, 236, 367), located within 5-HT receptors play the most important role in ligands binding. This information made it possible to think out a hypothetical model of drugserotonin receptor interaction, in which amino acids were introduced into the stationary phase of chromatographic environment [14]
Summary
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter in the central nervous system (CNS) that plays a significant role in migraine attacks, mood regulation, sleep, appetite, sexual function, anxiety treatment, depression, and schizophrenia This neurotransmitter interacts with fourteen serotoninergic receptor subtypes, which are classified into seven families (5-HT1−7). In the literature there are examples of biochromatographic data analyses, their implications for molecular pharmacology, and application in predicting pharmacological activity of drugs [25,26,27,28,29,30,31,32] In such studies are employed both parameters obtained from the experimental interaction with the environment (e.g., biochromatography) and calculated physicochemical parameters, which result from the construction of chemical compounds. The choice of model compounds for the binding elements in the receptor structure was based on the literature data on the use of propionic acid to mimic aspartic acid structure in interaction with the ligands of the histamine H3 receptor [33, 34]
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