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INFLAMMATION AND IMMUNOPHARMACOLOGY

A Novel Nonpeptide Antagonist of the Kinin B₁ Receptor: Effects at the Rabbit Receptor

Centre Hospitalier Universitaire de Québec, Centre de recherche, Québec, Canada

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 nonpeptide antagonist for the human B₁R, but it 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 it 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 extracellular signal-regulated kinase1/2 mitogen-activated protein 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 human embryonic kidney (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.

Address correspondence to: Dr. François Marceau, Centre Hospitalier Universitaire de Québec, Centre de recherche, Pavillon l'Hôtel-Dieu de Québec, 11 Côte-du-Palais, Québec, QC, Canada G1R 2J6. E-mail: francois.marceau{at}crhdq.ulaval.ca

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