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 (K(i)) 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 (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 B2 antagonist active in both bradykinin radioligand binding and functional assays.
|Number of pages||5|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - May 24 1994|