title: Pharmacological profile of histaprodifens at four recombinant histamine H1 receptor species isoforms.
abstract: There are differences in the pharmacological properties of phenylhistamines and histaprodifens between guinea pig histamine H(1) receptor (gpH(1)R) and human histamine H(1) receptor (hH(1)R). The aim of this study was to analyze species differences in more detail, focusing on histaprodifen derivatives and including the bovine histamine H(1) receptor (bH(1)R) and rat histamine H(1) receptor (rH(1)R). H(1)R species isoforms were coexpressed with the regulator of G protein signaling RGS4 in Sf9 insect cells. We performed [(3)H]mepyramine binding assays and steady-state GTPase assays. For a novel class of histaprodifens, the chiral histaprodifens, unique species differences between hH(1)R, bH(1)R, rH(1)R, and gpH(1)R were observed. The chiral histaprodifens 8R and 8S were both partial agonists at gpH(1)R, but only 8R was a partial agonist at the other H(1)R species isoforms. An additional phenyl group in chiral histaprodifens 10R and 10S, respectively, resulted in a switch from agonism at gpH(1)Rto antagonism at hH(1)R, bH(1)R, and rH(1)R. In general, histaprodifens showed the order of potency hH(1)R < bH(1)R < rH(1)R < gpH(1)R. An active-state model of gpH(1)R was generated with molecular dynamics simulations. Dimeric histaprodifen was docked into the binding pocket of gpH(1)R. 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 H(1)R species isoforms; 2) gpH(1)R and rH(1)R, on one hand, and hH(1)R and bH(1)R, on the other hand, resemble each other structurally and pharmacologically; and 3) histaprodifens interact with H(1)R at multiple sites.
authors.affiliation: Department of Pharmacology and Toxicology, University of Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Strasser
authors.forename: Birgit
authors.initials: B
authors.lastname: Striegl
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Wittmann
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D003001:Cloning, Molecular; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006168:Guinea Pigs; D006632:Histamine / Q000031:analogs & derivatives* / Q000378:metabolism*; D017442:Histamine Agonists / Q000378:metabolism*; D006634:Histamine H1 Antagonists / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D011738:Pyrilamine / Q000378:metabolism*; D051381:Rats; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D011994:Recombinant Proteins; C118994:histaprodifen; D006632:Histamine; D020558:GTP Phosphohydrolases; D011738:Pyrilamine