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

Abstract

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-quinolinyl) oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide) has been identified.

2. This compound displaced [³H]-BK binding to B₂ receptors present in guinea-pig ileum membranes with an IC₅₀ of 5.6×10⁻¹⁰ M and in rat uterus with an IC₅₀ 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 [³H]-BK binding to B₂ receptors with an IC₅₀ of 2.9×10⁻⁹ M and a K_i of 3.6×10⁻¹⁰ 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 7.9×10⁻⁹ 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 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.

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