Pharmacological characterization and radioligand binding properties of a high-affinity, nonpeptide, bradykinin B1 receptor antagonist

European Journal of Pharmacology
Richard W RansomMark G Bock

Abstract

Compound A (N-[2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl]-2-[(2R)-1-(2-napthylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetamide) is a member of a new class of aryl sulfonamide dihydroquinoxalinone bradykinin B1 receptor antagonists that should be useful pharmacological tools. Here we report on some of the pharmacological properties of compound A as well as the characterization of [35S]compound A as the first nonpeptide bradykinin B1 receptor radioligand. Compound A inhibited tritiated peptide ligand binding to the cloned human, rabbit, dog, and rat bradykinin B1 receptors expressed in CHO cells with Ki values of 0.016, 0.050, 0.56, and 29 nM, respectively. It was inactive at 10 microM in binding assays with the cloned human bradykinin B2 receptor. In functional antagonist assays with the cloned bradykinin B1 receptors, compound A inhibited agonist-induced signaling with activities consistent with the competition binding results, but had no antagonist activity at the bradykinin B2 receptor. Compound A was also found to be a potent antagonist in a rabbit aorta tissue bath preparation and to effectively block des-Arg9 bradykinin depressor responses in lipopolysaccharide-treated rabbit following intravenous administ...Continue Reading

References

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Citations

Feb 25, 2006·Biological Chemistry·J Fred HessDouglas J Pettibone
Feb 25, 2006·Biological Chemistry·Guillaume Morissette, François Marceau
Apr 21, 2009·Journal of Peptide Science : an Official Publication of the European Peptide Society·József HuszárGyörgy Keseru
Mar 8, 2005·Trends in Pharmacological Sciences·François Marceau
Apr 23, 2005·Biochemical and Biophysical Research Communications·Sookhee N HaFred J Hess
May 2, 2007·The Journal of Pharmacology and Experimental Therapeutics·Jon E HawkinsonAnnika B Malmberg
May 28, 2005·The Journal of Pharmacology and Experimental Therapeutics·Jean-Philippe FortinFrançois Marceau
Feb 3, 2005·British Journal of Pharmacology·Mark Connor, Christopher W Vaughan
Jul 12, 2007·Chemical Reviews·Jade S BlakeneyDavid P Fairlie

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