THE NONPEPTIDE WIN-64338 IS A BRADYKININ B-2 RECEPTOR ANTAGONIST

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 [H-3]- bradykinin binding to the bradykinin Bz receptor on human IMR-90 cells with a binding inhibition constant (K-i) of 64 +/- 8 nM and demonstrates competitive inhibition of bradykinin-stimulated Ca-45(2+) efflux from IMR-90 cells (pA(2) = 7.1). The antagonist inhibits bradykinin-mediated guinea pig ileum contractility (pA(2) = 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 B-1 receptor assay, demonstrating that it is a selective bradykinin B-2 receptor antagonist. The compound inhibits [H-3]quinuclidinyl benzilate binding to the rat brain muscarinic receptor (K-i = 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 B-2 antagonist active in both bradykinin radioligand binding and functional assays.