Contribution of Binding Enthalpy and Entropy to Affinity of Antagonist and Agonist Binding at Human and Guinea Pig Histamine H₁-Receptor

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 H 1 receptor (H 1 R). Because previous studies revealed species differences in pharmacology between human H 1 R (hH 1 R) and guinea pig H 1 R (gpH 1 R), we analyzed a broad spectrum of H 1 R antagonists and agonists at hH 1 R and gpH 1 R. [3 H]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 H 1 R in two different orientations. Our studies revealed significant species differences in binding enthalpy and entropy between hH 1 R and gpH 1 R 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 hH 1 R and gpH 1 R 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 hH 1 R nor gpH 1 R, but thermodynamic analysis of ligand-binding may be a novel approach to dissect agonist-and antagonist-specific receptor conformations.

Binding of Ligands to GPCRs ? How Valid is a Thermodynamic Discrimination of Antagonists and Agonists?

“…Mianserin for example was studied thermodynamically at the human and guinea-pig histamine H 1 receptor [13] and at the rat serotonin 5-HT 1A receptor [10]. At the hH 1 R, the enthalpy for ligand binding is 32.6 kJ/mol, whereas it is significantly higher at gpH 1 R with 72.2 kJ/mol.…”

“…For the histamine H 1 receptor, an extensive study, addressing the thermodynamics of ligand binding was performed at the human H 1 R and guinea-pig H 1 R (Figure 1) [13]. In general, the data reveals species differences, in dependence of the ligand, for the thermodynamic properties ΔH activity-studies, but also enthalpic and entropic terms of the ligand binding process [27].…”

“…At the histamine H 1 receptor [13], and the adrenergic β 2 receptor (hβ 2 R), the enthalpy and entropy of ligand binding was studied for chiral compounds, including both enantiomers [8,9]. As mentioned above, the enthalpy and entropy of desolvation of the ligand is suggested to have an influence onto enthalpy and entropy of ligand binding to a target.…”

“…Having a look on the efficacy and the pK i values of ligands at a GPCR, it is impossible to decide on antagonism or agonism using the pK i values or equivalently the Gibbs reference energy for the ligand-receptor binding (ΔG ο ). Taking into account the basic relation [13,24] …”

“…Weiland et al (1979) were the first, who observed a thermodynamic discrimination of antagonists and agonists at the β-adrenergic receptor [6]. Subsequently, a large number of studies at different GPCRs were performed in order to determine thermodynamics of ligand binding: For example, addressing the β 2 adrenergic receptor [6][7][8][9], the serotonin 5-HT 1A -receptor [10], the dopamine D 2 receptor [11,12], the histamine H 1 receptor [13] and the histamine H 3 receptor [14]. These receptors belong to the aminergic GPCRs of the GPCR family A [3].…”