title: CRTH2-specific binding characteristics of [3H]ramatroban and its effects on PGD2-, 15-deoxy-Delta12, 14-PGJ2- and indomethacin-induced agonist responses.
abstract: We previously showed that ramatroban (Baynastrade mark), a thromboxane A(2) (TxA(2)) antagonist, had inhibited prostaglandin D(2) (PGD(2))-stimulated human eosinophil migration mediated through activation of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). However, detailed pharmacological characterization of its inhibitory activity has not been described. In the present study, we showed that [(3)H]ramatroban bound to a single receptor site on CRTH2 transfectants with a similar K(d) value (7.2 nM) to a TxA(2) receptor (8.7 nM). We also demonstrated that ramatroban inhibited PGD(2)-, 15-deoxy-Delta(12, 14)-PGJ(2) (15d-PGJ(2))- and indomethacin-induced calcium responses on CRTH2 transfectants in a competitive manner with similar pA(2) values (8.5, 8.5, and 8.6, respectively). This is the first report showing the evidence for direct binding of ramatroban to CRTH2, revealing its competitive inhibitory effects and another interesting finding that PGD(2), indomethacin and 15d-PGJ(2) share the same binding site with ramatroban on CRTH2.
authors.affiliation: Respiratory Diseases Research, Bayer Yakuhin, Ltd., Kizu-cho, Soraku-gun, Kyoto, Japan. hiromi.sugimoto@pfizer.com
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Michitaka
authors.initials: M
authors.lastname: Shichijo
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Okano
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Bacon
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001667:Binding, Competitive; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology*; D008954:Models, Biological; D010421:Pentanoic Acids / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection; D014316:Tritium
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002227:Carbazoles; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010421:Pentanoic Acids; D011725:Pyridines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; D014316:Tritium; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D000242:Cyclic AMP; C063119:ramatroban; C060219:ridogrel; D015230:Prostaglandin D2; D002118:Calcium; D007213:Indomethacin; C036293:prostaglandin D2 receptor