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.
Morissette
Guillaume
G
Centre Hospitalier Universitaire de Québec, Centre de recherche, Pavillon l'Hôtel-Dieu de Québec, 11 Côte-du-Palais, Québec, QC, Canada G1R 2J6.
Fortin
Jean-Philippe
JP
Otis
Sophie
S
Bouthillier
Johanne
J
Marceau
François
F
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