Schnell, David and Strasser, Andrea and Seifert, Roland (2010) Comparison of the pharmacological properties of human and rat histamine H-3-receptors. BIOCHEMICAL PHARMACOLOGY, 80 (9). pp. 1437-1449. ISSN 0006-2952,
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Ligand pharmacology of histamine H-3-receptors is species-dependent. In previous studies, two amino acids in transmembrane domain 3 (TM III) were shown to play a significant role. In this study, we characterized human and rat histamine H-3-receptors (hH(3)R and rH(3)R, respectively), co-expressed with mammalian G proteins in Sf9 insect cell membranes. We compared a series of imidazole-containing H3R ligands in radioligand binding and steady-state GTPase assays. H(3)Rs similarly coupled to G alpha(i/o)-proteins. Affinities and potencies of the agonists histamine, N-alpha-methylhistamine and R-(alpha)-methylhistamine were in the same range. Imetit was only a partial agonist. The pharmacology of imetit and proxifan was similar at both species. However, impentamine was more potent and efficacious at rH(3)R. The inverse agonists ciproxifan and thioperamide showed higher potency but lower efficacy at rH(3)R. Clobenpropit was not species-selective. Strikingly, imoproxifan was almost full agonist at hH(3)R, but an inverse agonist at rH(3)R. Imoproxifan was docked into the binding pocket of inactive and active hH(3)R- and rH(3)R-models and molecular dynamic simulations were performed. Imoproxifan bound to hH(3)R and rH(3)R in E-configuration, which represents the trans-isomer of the oxime-moiety as determined in crystallization studies, and stabilized active hH(3)R-, but inactive rH(3)R-conformations. Large differences in electrostatic surfaces between TM III and TM V cause differential orientation of the oxime-moiety of imoproxifan, which then differently interacts with the rotamer toggle switch Trp(6.48) in TM VI. Collectively, the substantial species differences at H(3)Rs are explained at a molecular level by the use of novel H3R active-state models. (C) 2010 Elsevier Inc. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-COUPLED RECEPTOR; HIGH CONSTITUTIVE ACTIVITY; GUANIDINE-TYPE AGONISTS; H-3 RECEPTOR; CRYSTAL-STRUCTURE; GUINEA-PIG; H-1-RECEPTOR; HETEROGENEITY; SELECTIVITY; ANTAGONIST; Active receptor state; Histamine H-3-receptor; Imoproxifan; Molecular dynamics simulations; Sf9 insect cells |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 Jul 2020 06:20 |
| Last Modified: | 07 Jul 2020 06:20 |
| URI: | https://pred.uni-regensburg.de/id/eprint/23916 |
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