title: The nonpeptide WIN 64338 is a bradykinin B2 receptor antagonist.
abstract: We report the synthesis and in vitro biological activity of the nonpeptide bradykinin receptor antagonist WIN 64338, [[4-[[2-[[bis(cyclohexylamino)methylene]amino]-3-(2- naphthyl)-1-oxopropyl]amino]phenyl]methyl]tributylphosphonium chloride monohydrochloride. WIN 64338 inhibits [3H]-bradykinin binding to the bradykinin B2 receptor on human IMR-90 cells with a binding inhibition constant (Ki) of 64 +/- 8 nM and demonstrates competitive inhibition of bradykinin-stimulated 45Ca2+ efflux from IMR-90 cells (pA2 = 7.1). The antagonist inhibits bradykinin-mediated guinea pig ileum contractility (pA2 = 8.2) and has significantly weaker activity against acetylcholine-induced contractility in the same preparation. WIN 64338 is not active in a rabbit aorta bradykinin B1 receptor assay, demonstrating that it is a selective bradykinin B2 receptor antagonist. The compound inhibits [3H]quinuclidinyl benzilate binding to the rat brain muscarinic receptor (Ki = 350 nM) but is 25- to 100-fold more selective for the bradykinin receptor compared with other receptors against which it has been tested. Synthesis of WIN 64338 has provided a nonpeptide competitive bradykinin B2 antagonist active in both bradykinin radioligand binding and functional assays.
authors.affiliation: Department of Enzymology and Receptor Biochemistry, Sterling Winthrop Pharmaceuticals Research Division, Collegeville, PA 19426.
authors.forename: D G
authors.initials: DG
authors.lastname: Sawutz
authors.forename: J M
authors.initials: JM
authors.lastname: Salvino
authors.forename: R E
authors.initials: RE
authors.lastname: Dolle
authors.forename: F
authors.initials: F
authors.lastname: Casiano
authors.forename: S J
authors.initials: SJ
authors.lastname: Ward
authors.forename: W T
authors.initials: WT
authors.lastname: Houck
authors.forename: D M
authors.initials: DM
authors.lastname: Faunce
authors.forename: B D
authors.initials: BD
authors.lastname: Douty
authors.forename: E
authors.initials: E
authors.lastname: Baizman
authors.forename: M M
authors.initials: MM
authors.lastname: Awad
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D065168:Bradykinin Receptor Antagonists; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006168:Guinea Pigs; D006801:Humans; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*
chemical_list: D065168:Bradykinin Receptor Antagonists; D009281:Naphthalenes; D009943:Organophosphorus Compounds; C087374:WIN 64338; D002118:Calcium