A Novel Nonpeptide Antagonist of the Kinin B₁Receptor: Effects at the Rabbit Receptor

Abstract

The kinin B 1 receptor (B 1 R) has attracted interest as a potential therapeutic target because this inducible G protein-coupled receptor is involved in sustained inflammation and inflammatory pain production.is a high-affinity nonpeptide antagonist for the human B 1 R, but it is potent at the rabbit B 1 R as well: its K i value for the inhibition of [ The kinin B 1 receptor (B 1 R) is a G protein-coupled receptor selectively stimulated by sequences related to bradykinin (BK) but not by BK itself. Instead, des-Arg 9 -BK, Lys-BK (kallidin) and Lys-des-Arg 9 -BK (des-Arg 10

Role of Nuclear Factor-κB and Protein Kinase C Signaling in the Expression of the Kinin B1Receptor in Human Vascular Smooth Muscle Cells

“…This effect was also seen with IL-1␤ and PMA, with a nonsignificant concentration decrease with actinomycin D treatment. The B 1 receptor agonist Lys-des-Arg 9 -BK had no significant effect on B 1 receptor mRNA concentration (with or without actinomycin D); compound 11 (100 nM, data not shown), a high affinity nonpeptide antagonist of the B 1 receptor (Morissette et al, 2004), had no effect as well.…”

Fluorescent Ligands of the Bradykinin B1 Receptors: Pharmacologic Characterization and Application to the Study of Agonist-Induced Receptor Translocation and Cell Surface Receptor Expression

“…However, Sabourin et al (2002) have observed a special form of agonist-induced translocation using a fusion protein composed of the rabbit B 1 receptor conjugated to the yellow fluorescent protein (B 1 R-YFP): the smooth membrane distribution of the receptor-associated fluorescence evolved toward condensed structures that remained associated with the plasma membrane. This translocation was inhibited by pharmacological antagonists of the B 1 receptors, showing that this response is dependent on a form of signaling, and also by cell pretreatment with ␤-cyclodextrin, supporting that the structures where B 1 R-YFP concentrate are a variety of cholesterol-rich rafts (Sabourin et al, 2002;Morissette et al, 2004). Furthermore, unlike the stable B 2 receptors, the B 1 receptors are apparently short-lived at the cell surface, where they are cleared in a ligand-independent manner (Fortin et al, 2003).…”

“…Staining by fluorescent antagonists was not conferred by the empty FLAG vector and was greatly reduced by cotreating receptorexpressing cells with the high-affinity nonpeptide antagonist, compound 11 (Fig. 4) (Morissette et al, 2004). The B 1 receptor agonist B-10378 also labeled cells that expressed recombinant B 1 R-FLAG or rabbit B 1 receptors (50 nM, 30-min treatment, Fig.…”

“…Table 1) were synthesized, purified, and characterized using general methods described elsewhere (Gera et al, 1996). Compound 11 is a powerful nonpeptide antagonist at the human and rabbit B 1 receptors (Morissette et al, 2004) receptor extended with a C-terminal FLAG epitope and for the wildtype rabbit B 1 receptor has been described previously (Larrivée et al, 2000;Morissette et al, 2008). The empty FLAG vector (without a start codon, gift from Dr. Patrick Provost, Centre Hospitalier Universitaire de Québec, Quebec City, QC, Canada) was used in some control experiments.…”

Met-Lys-bradykinin-Ser-Ser, a peptide produced by the neutrophil from kininogen, is metabolically activated by angiotensin converting enzyme in vascular tissue

“…1A). Tissue treatment with the powerful and specific nonpeptide B 1 receptor antagonist, compound 11 (1 nM) [18], shifted the concentration-effect of Lys-des-Arg 9 -BK to the right and abolished the effect of the submaximal concentration of Met-Lys-BK-Ser-Ser, supporting that both agents contracted the tissue via B 1 receptors. The contractile effects of Met-Lys-BK-Ser-Ser or of Lys-des-Arg 9 -BK were not modified by co-incubation with the ACE inhibitor enalaprilat (100 nM inhibitor (1 µM), a blocker of arginine carboxypeptidases that removes the C-terminal arginine from native kinins ( Fig.…”