Molecular Basis for the Selective Interaction of Synthetic Agonists with the Human Histamine H1-Receptor Compared with the Guinea Pig H1-Receptor

Abstract

Previous studies revealed that phenylhistamines and histaprodifens possess higher potency and affinity at guinea pig histamine H 1 -receptor (gpH 1 R) than at human histamine H 1 -receptor (hH 1 R). However, we recently identified an imidazolylpropyl-with higher potency and efficacy at hH 1 R compared with gpH 1 R. The aim of this study was to reveal the molecular basis for the species differences of synthetic ligands. We studied 11 novel phenylhistamines and phenoprodifens. H 1 R species isoforms were expressed in Sf9 insect cells, and [3 H]mepyramine competition binding and GTPase assays were performed. We identified bulky phenylhistamines with higher potency and affinity at hH 1 R compared with gpH 1 R. Molecular dynamics simulations of ligand-H 1 R interactions revealed four potential binding modes for phenylhistamines possessing an additional histamine moiety; the terminal histamine moiety showed a high flexibility in the binding pocket. There are striking similarities in ligand properties in bulky phenylhistamines and UR-AK57. Comparison of bulky phenylhistamine binding mode with binding mode of UR-AK57 suggests that only one of these four binding modes should be established. The higher potency is explained by more effective van der Waals interaction of the compounds with Asn 2.61 (hH 1 R) relative to Ser 2.61 (gpH 1 R). In addition, two stable binding modes for phenoprodifens with different orientations in the binding-pocket were identified. Depending on phenoprodifen orientation, the highly conserved Trp 6.48 , part of the toggle switch involved in receptor activation, was found in an inactive or active conformation, respectively. We identified the first phenylhistamines with higher potency at hH 1 R than at gpH 1 R and obtained insight into the binding mode of bulky phenylhistamines and imidazolylpropylguanidines.

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

“…In contrast, for the (S)-phenylhistamin (exact: (S)-1-(2-phenyl-1H-imidazol-4-yl)propan-2-amine), a negative enthalpy of binding and entropy of binding (-TΔS) was observed at hH 1 R and gpH 1 R. Thus, the binding of (R)-phenylhistamine is entropy-driven, whereas the binding of the (S)-phenylhistamine is entropy-and slightly enthalpydriven. The efficacies between the (R)-and (S)-phenylhistamine are not significantly different at hH 1 R (E max , (R): 0.21, (S): 0.23) or gpH 1 R (E max , (R): 0.51, (S): 0.78) [28]. Thus, it may be concluded, that the differences in enthalpy and entropy between the (R)-and (S)-phenylhistamine can be related with the different binding conformation of both ligands due to the difference induced by the center of chirality.…”

“…Additionally, a different number of water molecules may be located in the binding pocket and act as mediator of interaction between the ligand and the receptor. The interpretation of the data with regard to the chiral phenoprodifens is more complicated, since the phenoprodifens are suggested to bind in two different orientations into the binding pocket of the histamine H 1 receptor [13,28] cpd. The data are calculated using the Eyring equation and the rate constants for association [34].…”

“…diphenylpropyl)-1H-imidazol-4-yl)ethyl-1-(2-phenyl-1H-imidazol-4-yl)propan-2-amine) act as antagonist at hH 1 R (E max , (R): 0.05, ( S ): 0.04) and as partial agonist at gpH 1 R (E max , (R): 0.60, (S): 0.23) [28]. For hH 1 R or gpH 1 R, no large differences for the enthalpic and entropic term of ligand binding were observed between the (R)-and (S)-phenoprodifen [13].…”

“…However, for the hH 1 R and gpH 1 R, a correlation of the enthalpic or entropic terms for ligand binding with the experimentally determined efficacy is presented (Figure 4) [13,28,35]. These data show that there is no clear "thermodynamic discrimination" of antagonists and agonists at hH 1 R and gpH 1 R. However, the following tendency can be observed: With increasing efficacy (E max ) in the series antagonist (E max =0) → partial agonist (0<E max <100) → full agonist (E max =100), the enthalpic term decreases, whereas the entropic term increases (Figure 4).…”

Comparison of the pharmacological properties of human and rat histamine H3-receptors

“…Some of them show unique behaviours, like epimeric members of the ergoline family or chiral histaprodifens, switching from silent antagonism to partial agonism depending on the species studied [28,43]. Detailed molecular studies dissected some of the underlying mechanisms [26,44]. At the H 2 R, bulky agonists like the long-chained impromidine-and arpromidine-derived guanidines or N G -acylated imidazolylpropylguanidines (AIPGs), are more potent and efficacious at the gpH 2 R than at the hH 2 R [37,45].…”