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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 May 24;91(11):4693–4697. doi: 10.1073/pnas.91.11.4693

The nonpeptide WIN 64338 is a bradykinin B2 receptor antagonist.

D G Sawutz 1, J M Salvino 1, R E Dolle 1, F Casiano 1, S J Ward 1, W T Houck 1, D M Faunce 1, B D Douty 1, E Baizman 1, M M Awad 1, et al.
PMCID: PMC43854  PMID: 8197121

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.

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Selected References

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