A novel nonpeptide antagonist of the kinin B1 receptor: effects at the rabbit receptor.
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 Ki 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.
Centre Hospitalier Universitaire de Québec, Centre de recherche, Pavillon l'Hôtel-Dieu de Québec, 11 Côte-du-Palais, Québec, QC, Canada G1R 2J6.
Guillaume
G
Morissette
Jean-Philippe
JP
Fortin
Sophie
S
Otis
Johanne
J
Bouthillier
François
F
Marceau
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D015153:Blotting, Western; D065169:Bradykinin B1 Receptor Antagonists; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D000939:Epitopes / Q000235:genetics; D016259:Genes, myc / Q000235:genetics; D019044:Image Cytometry; D066298:In Vitro Techniques; D018613:Microscopy, Confocal; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D017510:Protein Folding; D011810:Quinoxalines / Q000494:pharmacology*; D011817:Rabbits; D043783:Receptor, Bradykinin B1 / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D013450:Sulfones / Q000494:pharmacology*
C495034:2-(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; D065169:Bradykinin B1 Receptor Antagonists; D000939:Epitopes; D011810:Quinoxalines; D043783:Receptor, Bradykinin B1; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones