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 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.
Footnotes
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This study was supported by the Canadian Institutes of Health Research (Grant MOP-14077) and the Fonds de la recherche en Santé du Québec (Studentship award to J.-P.F.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.104.071266.
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ABBREVIATIONS: B1R, B1 receptor; B2R, B2 receptor; BK, bradykinin; YFP, yellow fluorescent protein; Ang II, angiotensin II; AT1R, AT1 receptor; DMSO, dimethyl sulfoxide; PG, prostaglandin; 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; COX, cyclooxygenase; PCR, polymerase chain reaction; HEK, human embryonic kidney; EGF, epidermal growth factor; ERK, extracellular signal-regulated kinase; MAP, mitogen-activated protein; NS-398, N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide; SC-560, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl pyrazole; SSR240612, (2R)-2-[((3R)-3-(1,3-benzodioxol-5-yl)-3-{[(6-methoxy-2-naphtyl)sulfonyl]amino}propanoyl)amino]-3-(4-{[2R,6S)-2,6-dimethylpiperidinyl]methyl}phenyl)-N-isopropyl-N-methylpropanamide hydrochloride.
- Received May 11, 2004.
- Accepted July 26, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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