Abstract
For several GPCRs, discrimination between agonism and antagonism is possible on the basis of thermodynamics parameters, such as binding enthalpy and entropy. In this study, we analyze whether agonists and antagonists can also be discriminated thermodynamically at the histamine H1 receptor (H1R). Because previous studies revealed species differences in pharmacology between human H1R (hH1R) and guinea pig H1R (gpH1R), we analyzed a broad spectrum of H1R antagonists and agonists at hH1R and gpH1R. [3H]Mepyramine competition binding assay were performed at five different temperatures in a range from 283.15 to 303.15 K. In addition, we performed a temperature-dependent three-dimensional quantitative structure activity relationship study to predict binding enthalpy and entropy for histaprodifen derivatives, which can bind to H1R in two different orientations. Our studies revealed significant species differences in binding enthalpy and entropy between hH1R and gpH1R for some antagonists and agonists. Furthermore, in some cases, we found changes in heat capacity of the binding process that were different from zero. Differences in flexibility of the ligands may be responsible for this observation. For most ligands, the binding process to hH1R and gpH1R is clearly entropy-driven. In contrast, for the endogenous ligand histamine, the binding process is significantly enthalpy-driven at both species isoforms. Thus, a definite discrimination between antagonism and agonism based on thermodynamic parameters is possible for neither hH1R nor gpH1R, but thermodynamic analysis of ligand-binding may be a novel approach to dissect agonist- and antagonist-specific receptor conformations.
Footnotes
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This work was supported by the Research Training Program (Graduiertenkolleg) [Grant GRK760] “Medicinal Chemistry: Molecular Recognition—Ligand-Receptor Interactions” of the Deutsche Forschungsgemeinschaft.
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ABBREVIATIONS: H1R, histamine H1-receptor; gp, guinea pig; h, human; GPCR, G-protein coupled receptor; 5-HT, 5-hydroxytryptamine; 3D-QSAR, three-dimensional quantitative structure activity relationship.
- Accepted April 3, 2009.
- Received February 9, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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