The identification of an orally active, nonpeptide bradykinin B 2 receptor antagonist, FR173657

1 An orally active, nonpeptide bradykinin (BK) B 2 receptor antagonist, FR173657 (E)‐3‐(6‐acetamido‐3‐pyridyl)‐N‐[N‐[2‐4‐dichloro‐3‐[(2‐methyl‐8‐quinolinyl) oxymethyl]phenyl]‐N‐methylaminocarbonyl‐methyl]acrylamide) has been identified. 2 This compound displaced [ 3 H]‐BK binding to B 2 receptors present in guinea‐pig ileum membranes with an IC 50 of 5.6 × 10 −10 M and in rat uterus with an IC 50 of 1.5 × 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 [ 3 H]‐BK binding to B 2 receptors with an IC 50 of 2.9 × 10 −9 M and a K i of 3.6 × 10 −10 M, but did not reduce [ 3 H]‐des‐Arg 10 ‐kallidin binding to B 1 , receptors. 4 In guinea‐pig isolated preparations, FR173657 antagonized BK‐induced contractions with an IC 50 of 7.9 × 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 × 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 pA 2 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 ED 50 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 ED 50 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 B 2 receptor antagonist.