The nonpeptide WIN 64338 is a bradykinin B2 receptor antagonist

David G. Sawutz, Joseph M. Salvino, Roland E. Dolle, Fran Casiano, Susan J. Ward, Wayne T. Houck, David M. Faunce, Brent D. Douty, Eugene Baizman, Mohammed M.A. Awad, François Marceau, Peter R. Seoane

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92 Scopus citations


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.

Original languageEnglish
Pages (from-to)4693-4697
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number11
StatePublished - May 24 1994


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