The nonpeptide WIN 64338 is a bradykinin B2 receptor antagonist (original) (raw)

We report the synthesis and in vitro biological activity of the nonpeptide bradykinin receptor antagonist WIN 64338, [[4-[[2-[[bis(cyclohexylamino)methylenelamino]-3-(2naphthyl)-l-oxopropyl]amlno]phenyl]methyl]tributylphosphonium chloride monohydrochloide. WIN 64338 inhibits [3H1bradykinin binding to the bradykinin B2 receptor on human IMR-90 cells with a binding hibition constant (K) of64 ± 8 nM and demonstrates competitive inhibition of bradykininstimulated Ca2+ efflux from IMR-90 cells (pA2 = 7.1). The antagonist inhibits bradykinin-mediated guinea pig ileum contractility (pA2 = 8.2) and has sificanty weaker activity against acetyicholine-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 antaist. The compound inhibits [3Hjquinuclldinyl benzllate binding to the rat brain muscarinic receptor (Ki = 350 nM) but is 25to 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.