title: The noncompetitive antagonism of histamine H1 receptors expressed in Chinese hamster ovary cells by olopatadine hydrochloride: its potency and molecular mechanism.
abstract: Calcium responses to various concentrations of histamine were monitored in Chinese hamster ovary cells stably expressing the human histamine H(1) receptor. The effects of various histamine H(1) receptor antagonists on the dose-response curve for histamine were evaluated. Olopatadine hydrochloride (olopatadine) inhibited the histamine-induced maximum response (pD(2)': 7.5) but had insignificant effects on histamine EC(50) values. This noncompetitive property exhibited by olopatadine, which was also observed in human umbilical vein endothelial cells, was the most striking among the antihistamines tested in this study. The geometrical isomer of olopatadine (E-isomer), which had a similar binding affinity to the histamine H(1) receptor as olopatadine, showed a mixed antagonistic profile (competitive and noncompetitive). These results indicate that the geometry around the double bond in the dimethylaminopropylidene group is critical for the potent noncompetitive property of olopatadine. Furthermore, binding mode analyses suggest that the protonated amine group in the dimethylaminopropylidene moiety of olopatadine forms an ionic bond with Glu 181 that is present in the second extracellular loop of the histamine H(1) receptor, whereas the amine group of the E-isomer does not. The second extracellular loop in aminergic G-protein-coupled receptors contributes to ligand binding and therefore the noncompetitive property of olopatadine may be explained by the interaction with Glu 181.
authors.affiliation: Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Jun
authors.initials: J
authors.lastname: Funahashi
authors.forename: Kiyotoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Kozue
authors.initials: K
authors.lastname: Hayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yano
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003990:Dibenzoxepins / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells; D006632:Histamine / Q000008:administration & dosage; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D007536:Isomerism; D000069605:Olopatadine Hydrochloride; D011485:Protein Binding; D011969:Receptors, Histamine H1 / Q000187:drug effects* / Q000378:metabolism; D014471:Umbilical Veins
chemical_list: D003990:Dibenzoxepins; D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D000069605:Olopatadine Hydrochloride; D006632:Histamine; D002118:Calcium