The identification of an orally active, nonpeptide bradykinin B2 receptor antagonist, FR173657

Br J Pharmacol. 1997 Feb;120(4):617-24. doi: 10.1038/sj.bjp.0700955.


1. An orally active, nonpeptide bradykinin (BK) B2 receptor antagonist, FR173657 (E)-3-(6-acetamido-3-pyridyl)-N-[N-[2-4-dichloro-3-[(2-methyl-8-quinolin yl) oxymethyl]phenyl]-N-methylaminocarbonyl-methyl] acrylamide) has been identified. 2. This compound displaced [3H]-BK binding to B2 receptors present in guinea-pig ileum membranes with an IC50 of 5.6 x 10(-10) M and in rat uterus with an IC50 of 1.5 x 10(-9) M. It did not inhibit different specific radio-ligand binding to other receptor sites. 3. In human lung fibroblast IMR-90 cells, FR173657 displaced [3H]-BK binding to B2 receptors with an IC50 of 2.9 x 10(-9) M and a Ki of 3.6 x 10(-10) M, but did not reduce [3H]-des]Arg10-kallidin binding to B1 receptors. 4. In guinea-pig isolated preparations, FR173657 antagonized BK-induced contractions with an IC50 of 7.9 x 10(-9) M, but did not antagonize acetylcholine or histamine-induced contractions even at a concentration of 10(-6) M. FR173657 caused parallel rightward shifts of the concentration-response curves to BK at concentrations of 10(-9) M and 3.2 x 10(-9) M, and a little depression of the maximal response in addition to the parallel rightward shift of the concentration-response curve at a concentration of 10(-8) M. Analysis of the data yield a pA2 of 9.2 +/- 0.2 (n = 5) and a slope of 1.5 +/- 0.2 (n = 5). 5. In vivo, the oral administration of FR173657 inhibited BK-induced bronchoconstriction dose-dependently in guinea-pigs with an ED50 of 0.075 mg kg-1, but did not inhibit histamine-induced bronchoconstriction even at 1 mg kg-1. FR173657 also inhibited carrageenin-induced paw oedema with an ED50 of 6.8 mg kg-1 2 h after the carrageenin injection in rats. 6. These results show that FR173657 is a potent, selective, and orally active bradykinin B2 receptor antagonist.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Bradykinin / antagonists & inhibitors
  • Bradykinin Receptor Antagonists*
  • Bronchoconstriction / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Female
  • Guinea Pigs
  • Humans
  • Ileum / drug effects
  • Ileum / metabolism
  • Inflammation / prevention & control
  • Male
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism
  • Quinolines / administration & dosage*
  • Quinolines / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Bradykinin B2
  • Receptors, Bradykinin / metabolism
  • Uterus / metabolism


  • Bradykinin Receptor Antagonists
  • FR 173657
  • Quinolines
  • Receptor, Bradykinin B2
  • Receptors, Bradykinin
  • Bradykinin