Abstract
Previous studies revealed that phenylhistamines and histaprodifens possess higher potency and affinity at guinea pig histamine H1-receptor (gpH1R) than at human histamine H1-receptor (hH1R). However, we recently identified an imidazolylpropylguanidine [N1-(3-cyclohexylbutanoyl)-N2-[3-(1H-imidazol-4-yl)-propyl]guanidine (UR-AK57)] with higher potency and efficacy at hH1R compared with gpH1R. 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. H1R species isoforms were expressed in Sf9 insect cells, and [3H]mepyramine competition binding and GTPase assays were performed. We identified bulky phenylhistamines with higher potency and affinity at hH1R compared with gpH1R. Molecular dynamics simulations of ligand-H1R 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 Asn2.61 (hH1R) relative to Ser2.61 (gpH1R). In addition, two stable binding modes for phenoprodifens with different orientations in the binding-pocket were identified. Depending on phenoprodifen orientation, the highly conserved Trp6.48, 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 hH1R than at gpH1R and obtained insight into the binding mode of bulky phenylhistamines and imidazolylpropylguanidines.
Footnotes
-
This work was supported by the Deutsche Forschungsgemeinschaft [Grant GRK760] and by the Research Training Program (Graduiertenkolleg) “Medicinal Chemistry: Molecular Recognition-Ligand-Receptor Interactions.”
-
ABBREVIATIONS: GPCR, G-protein-coupled receptor; HnR, histamine Hn receptor (where n is 1-4); UR-AK57, N1-(3-cyclohexylbutanoyl)-N2-[3-(1H-imidazol-4-yl)propyl]guanidine; h, human; gp, guinea pig; b, bovine; r, rat; MD, molecular dynamics; TM, transmembrane domain; hH2R-GsαS, fusion protein of the human histamine H2R and the short splice variant of Gsα.
-
↵1 Current affiliation: Abbott GmbH and Co. KG, Wiesbaden, Germany.
- Received October 23, 2008.
- Accepted December 1, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|