PHARMACOLOGICAL CHARACTERIZATION OF A NONPEPTIDE BRADYKININ B-2 RECEPTOR ANTAGONIST, FR165649, AND AGONIST, FR190997

1 The nonpeptide bradykinin (BK) B-2 receptor antagonist, FR165649 ety l]-N-methylamino]benzyloxyl-2-methylquinoline), and agonist, FR190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl) ]benzyloxy]-2-methyl- 4-(2-pyridylmethoxy)quinoline have been identified. These compounds ha ve a common chemical structure, and the 2-pyridylmethoxy group is the only structural difference between them. 2 Both FR165649 and FR190997 displaced [H-3]-BK binding to B-2 receptors in guinea-pig ileum membra nes, with an IC50 of 4.7 x 10(-10) M and 1.5 x 10(-9) M, respectively. They also displaced [H-3]-BK binding to B-2 receptors in human lung f ibroblast IMR-90 cells, with an IC50 of 1.6 X 10(-9) M and 9.8 x 10(-1 0) M, respectively. 3 In guinea-pig isolated ileum-preparations, FR165 649 had no agonistic effect on contraction and caused parallel rightwa rd shifts of the concentration-response curves to BK on contraction. A nalysis of the data produced a nominal pA(2) value of 9.2+/-0.1 (n = 5 ) and a slope of 1.4+/-0.1 (n = 5). On the other hand, FR190997 induce d concentration-dependent contraction of guinea-pig ilea with a pD(2) of 7.9+/-0.2 and the contraction was inhibited by a specific peptide b radykinin B-2 receptor antagonist, Hoe 140 (D-Arg-[Hyp(3), Thi(5), D-T ic(7), Oic(8)]BK) in a non-competitive manner. 4 In IMR-90 cells, FR16 5649 had no agonistic effect on phosphatidyl inositol (PI) hydrolysis and caused parallel rightward shifts (approximately 200 fold shift at 10(-7) M) of the concentration-response curves to BK on PI hydrolysis. FR190997 induced concentration-dependent PI hydrolysis in IMR-90 cell s with a pD(2) of 8.4+/-0.1, and this effect was inhibited by Hoe 140. 5 These results indicate that FR165649 and FR190997 are, respectively , a potent bradykinin B-2 receptor antagonist and agonist, and that th e agonistic activity depends on the small part of the nonpeptide ligan d. FR165649 and FR190997 may be useful tools for studying the relation ship between ligands and receptors.