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-methylaminocarbonylmethyl]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