QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.107.129601v1 324/1/60    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Straßer, A. Articles by Seifert, R. Search for Related Content PubMed PubMed Citation Articles by Straßer, A. Articles by Seifert, R.

CELLULAR AND MOLECULAR

Pharmacological Profile of Histaprodifens at Four Recombinant Histamine H₁ Receptor Species Isoforms

Department of Pharmaceutical/Medicinal Chemistry I, School of Pharmacy, University of Regensburg, Regensburg, Germany (A.S., B.S.); Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany (H.-J.W.); and Department of Pharmacology and Toxicology, School of Pharmacy, University of Regensburg, Regensburg, Germany (R.S.)

There are differences in the pharmacological properties of phenylhistamines and histaprodifens between guinea pig histamine H₁ receptor (gpH₁R) and human histamine H₁ receptor (hH₁R). The aim of this study was to analyze species differences in more detail, focusing on histaprodifen derivatives and including the bovine histamine H₁ receptor (bH₁R) and rat histamine H₁ receptor (rH₁R). H₁R species isoforms were coexpressed with the regulator of G protein signaling RGS4 in Sf9 insect cells. We performed [³H]mepyramine binding assays and steady-state GTPase assays. For a novel class of histaprodifens, the chiral histaprodifens, unique species differences between hH₁R, bH₁R, rH₁R, and gpH₁R were observed. The chiral histaprodifens 8R and 8S were both partial agonists at gpH₁R, but only 8R was a partial agonist at the other H₁R species isoforms. An additional phenyl group in chiral histaprodifens 10R and 10S, respectively, resulted in a switch from agonism at gpH₁Rto antagonism at hH₁R, bH₁R, and rH₁R. In general, histaprodifens showed the order of potency hH₁R < bH₁R < rH₁R < gpH₁R. An active-state model of gpH₁R was generated with molecular dynamics simulations. Dimeric histaprodifen was docked into the binding pocket of gpH₁R. Hydrogen bonds and electrostatic interactions were detected between dimeric histaprodifen and Asp-116, Ser-120, Lys-187, Glu-190, and Tyr-432. We conclude the following: 1) chiral histaprodifens interact differentially with H₁R species isoforms; 2) gpH₁R and rH₁R, on one hand, and hH₁R and bH₁R, on the other hand, resemble each other structurally and pharmacologically; and 3) histaprodifens interact with H₁R at multiple sites.

Address correspondence to: Dr. Roland Seifert, Department of Pharmacology and Toxicology, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany. E-mail: roland.seifert{at}chemie.uni-regensburg.de

This article has been cited by other articles:

				K.-F. Deml, S. Beermann, D. Neumann, A. Strasser, and R. Seifert Interactions of Histamine H1-Receptor Agonists and Antagonists with the Human Histamine H4-Receptor Mol. Pharmacol., November 1, 2009; 76(5): 1019 - 1030. [Abstract] [Full Text] [PDF]

				H.-J. Wittmann, R. Seifert, and A. Strasser Contribution of Binding Enthalpy and Entropy to Affinity of Antagonist and Agonist Binding at Human and Guinea Pig Histamine H1-Receptor Mol. Pharmacol., July 1, 2009; 76(1): 25 - 37. [Abstract] [Full Text] [PDF]

				A. Strasser, H.-J. Wittmann, M. Kunze, S. Elz, and R. Seifert Molecular Basis for the Selective Interaction of Synthetic Agonists with the Human Histamine H1-Receptor Compared with the Guinea Pig H1-Receptor Mol. Pharmacol., March 1, 2009; 75(3): 454 - 465. [Abstract] [Full Text] [PDF]

				R. Seifert and S. Dove Functional Selectivity of GPCR Ligand Stereoisomers: New Pharmacological Opportunities Mol. Pharmacol., January 1, 2009; 75(1): 13 - 18. [Abstract] [Full Text] [PDF]

				A. Strasser, H.-J. Wittmann, and R. Seifert Ligand-Specific Contribution of the N Terminus and E2-Loop to Pharmacological Properties of the Histamine H1-Receptor J. Pharmacol. Exp. Ther., September 1, 2008; 326(3): 783 - 791. [Abstract] [Full Text] [PDF]