Ligand-Specific Contribution of the N Terminus and E2-Loop to Pharmacological Properties of the Histamine H₁-Receptor

Abstract

There are species differences between human histamine H 1 receptor (hH 1 R) and guinea pig (gp) histamine H 1 receptor (gpH 1 R) for phenylhistamines and histaprodifens. Several studies showed participation of the second extracellular loop (E2-loop) in ligand binding for some G protein-coupled receptors (GPCRs). Because there are large species differences in the amino acid sequence between hH 1 R and gpH 1 R for the N terminus and E2-loop, we generated chimeric hH 1 Rs with gp E2-loop (h gpE2 H 1 R) and gp N terminus and gp E2-loop (h gpNgpE2 H 1 R). hH 1 R, gpH 1 R, and chimeras were expressed in Sf9 insect cells. [3 H]Mepyramine binding assays and steadystate GTPase assays were performed. In the series hH 1 R Ͼ h gpE2 H 1 R Ͼ h gpNgpE2 H 1 R, we observed a significant decrease in potency of histamine 1 in the GTPase assay. For phenoprodifen 5 and the chiral phenoprodifens 6R and 6S, a significant decrease in affinity and potency was found in the series hH 1 R Ͼ h gpE2 H 1 R Ͼ h gpNgpE2 H 1 R. In addition, we constructed new active-state H 1 R models based on the crystal structure of the human ␤ 2 -adrenergic receptor (h␤ 2 AR). Compared with the H 1 R active-state models based on the crystal structure of bovine rhodopsin, the E2-loop differs in its contact to the ligand bound in the binding pocket. In the bovine rhodopsin-based model, the backbone carbonyl of Lys187 (gpH 1 R) interacts with large histaprodifens in the binding pocket, but in the h␤ 2 ARbased model, Lys187 (gpH 1 R) is located distantly from the binding pocket. In conclusion, the differences in N terminus and E2-loop between hH 1 R and gpH 1 R exert an influence on affinity and/or potency for histamine and phenoprodifens 5, 6R, and 6S.

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…Evidence for a role of Lys191 5.39 and extracellular domains of the H 1 receptor in ligand-receptor interactions has earlier been obtained by mutagenesis and molecular dynamics studies (Wieland et al, 1999;604 Gillard et al, 2002a;Strasser and Wittmann, 2007;Wittmann et al, 2011b). Insights into the molecular features governing agonist-induced H 1 receptor activation await the resolution of an active H 1 receptor X-ray structure and currently still rely on molecular modeling and/or mutagenesis studies (Ohta et al, 1994;Strasser et al, 2008b;Sansuk et al, 2011). Histamine is thought to bind the H 1 receptor with its protonated ethylamine side chain via Asp107 3.32 (Ohta et al, 1994), whereas the imidazole ring is thought to interact with Asn198 5.46 and Lys191 5.39 (Leurs et al, 1994a(Leurs et al, , 1995a.…”

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

“…1, 9-22) are used as tools to study the pharmacology and functionality of the H 1 R on a molecular level. Several classes of synthetic H 1 R agonists are known, including phenylhistamines Zingel et al, 1995), histaprodifens (Elz et al, 2000;Menghin et al, 2003), and phenoprodifens (Strasser et al, 2008b). Weiland et al (1979) were the first to find that antagonists and agonists can be thermodynamically discriminated at the ␤-adrenergic receptor.…”

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

“…Based on the active state model of guinea pig H 1 R (gpH 1 R) [25,26], an active model of hH 3 R was constructed by homology modelling. All models were refined and energetically minimized with SYBYL 7.0 (Tripos, St.…”

“…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].…”