Received for publication May 11, 2004.
Revised July 22, 2004.
Accepted for publication July 26, 2004.

A novel nonpeptide antagonist of the kinin B1 receptor: effects at the rabbit receptor

Abstract

The kinin B1 receptor (B1R) has attracted interest as a potential therapeutic target because this inducible G protein coupled receptor is involved in sustained inflammation and inflammatory pain production. Compound 11 (2-{(2R)-1-[(3,4-dichlorophenyl)sulfonyl]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl}-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}acetamide) is a high affinity non-peptide antagonist for the human B1R, but is potent at the rabbit B1R as well : its K_i value for the inhibition of [³H]Lys-des-Arg⁹-BK (bradykinin) binding to a novel myc-labeled rabbit B₁R expressed in COS-1 is 22 pM. In contractility tests (organ bath pharmacology), we found that Compound 11 is an apparently surmountable antagonist of des-Arg⁹-BK- or Lys-des-Arg⁹-BK-induced contraction of the rabbit isolated aorta (pA₂ values of 10.6 ± 0.14 and 10.4 ± 0.12, respectively). It did not influence contractions induced by angiotensin II in the rabbit aorta or by BK or histamine in the jugular vein, but suppressed the prostaglandin-mediated relaxant effect of des-Arg⁹-BK on the rabbit isolated mesenteric artery. Compound 11 (1 nM) inhibited both the phosphorylation of the ERK1/2 MAP kinases induced by Lys-des-Arg⁹-BK in serum-starved rabbit aortic smooth muscle cells and the agonist-induced translocation of the fusion protein B₁R-yellow fluorescent protein expressed in HEK 293 cells. Compound 11 does not importantly modify the expression of myc-B₁R over 24 h in HEK 293 cells (no detectable action as "pharmacological chaperone"). The present results support that Compound 11 is a potent and highly selective antagonist suitable for further investigations of the role of the kinin B1R in models of inflammation, pain and sepsis based on the rabbit.

Key words: Lys-des-Arg9-bradykinin, aorta, kinin B1 receptor, kinin B2 receptor, pharmacological chaperone, rabbit

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