title: Differential thermodynamic driving force of first- and second-generation antihistamines to determine their binding affinity for human H1 receptors.
abstract: Differential binding sites for first- and second-generation antihistamines were indicated on the basis of the crystal structure of human histamine H1 receptors. In this study, we evaluated differences between the thermodynamic driving forces of first- and second-generation antihistamines for human H1 receptors and their structural determinants. The binding enthalpy and entropy of 20 antihistamines were estimated with the van't Hoff equation using their dissociation constants obtained from their displacement curves against the binding of [(3)H]mepyramine to membrane preparations of Chinese hamster ovary cells expressing human H1 receptors at various temperatures from 4°C to 37°C. Structural determinants of antihistamines for their thermodynamic binding properties were assessed by quantitative structure-activity relationship (QSAR) analyses. We found that entropy-dependent binding was more evident in second- than first-generation antihistamines, resulting in enthalpy-entropy compensation between the binding forces of first- and second-generation antihistamines. QSAR analyses indicated that enthalpy-entropy compensation was determined by the sum of degrees, maximal electrostatic potentials, water-accessible surface area and hydrogen binding acceptor count of antihistamines to regulate their affinity for receptors. In conclusion, it was revealed that entropy-dependent hydrophobic interaction was more important in the binding of second-generation antihistamines, even though the hydrophilicity of second-generation antihistamines is generally increased. Furthermore, their structural determinants responsible for enthalpy-entropy compensation were explored by QSAR analyses. These findings may contribute to understanding the fundamental mechanisms of how the affinity of ligands for their receptors is regulated.
authors: Department of Pharmacodynamics, Meiji Pharmaceutical University, 2-522-1 Kiyose, Tokyo 204-8588, Japan. Electronic address: hishi@my-pharm.ac.jp.
authors: Shigeru
authors: S
authors: Hishinuma
authors: Department of Pharmacodynamics, Meiji Pharmaceutical University, 2-522-1 Kiyose, Tokyo 204-8588, Japan.
authors: Kenta
authors: K
authors: Sugawara
authors: Department of Clinical Pharmaceutics, Meiji Pharmaceutical University, 2-522-1 Kiyose, Tokyo 204-8588, Japan.
authors: Yoshihiro
authors: Y
authors: Uesawa
authors: Department of Molecular Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78-1 Shomachi, Tokushima 770-8505, Japan.
authors: Hiroyuki
authors: H
authors: Fukui
authors: Department of Pharmacodynamics, Meiji Pharmaceutical University, 2-522-1 Kiyose, Tokyo 204-8588, Japan.
authors: Masaru
authors: M
authors: Shoji
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019277:Entropy; D006633:Histamine Antagonists / Q000737:chemistry / Q000145:classification* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011485:Protein Binding; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D006633:Histamine Antagonists; D008024:Ligands; D011969:Receptors, Histamine H1
keywords: Affinity; Antihistamines; Enthalpy; Entropy; Histamine H(1) receptor