Pharmacological characterization of a nonpeptide bradykinin B 2 receptor antagonist, FR165649, and agonist, FR190997

The nonpeptide bradykinin (BK) B 2 receptor antagonist, FR165649 (8‐[2,6‐dichloro‐3‐[N‐[(E)‐4‐(N‐ methylcarbamoyl)cinnamidoacetyl] ‐N‐methylamino] benzyloxy] ‐2 ‐ methylquinoline), and agonist, FR190997 (8‐[2,6‐dichloro‐3‐[N‐[(E)‐4‐(N‐methylcarbamoyl) cinnamidoacetyl]‐N‐methylamino]benzyloxy]‐2‐methyl‐4‐(2‐pyridylmethoxy)quinoline) have been identified. These compounds have a common chemical structure, and the 2‐pyridylmethoxy group is the only structural difference between them. Both FR165649 and FR190997 displaced [ 3 H]‐BK binding to B 2 receptors in guinea‐pig ileum membranes, with an IC 50 of 4.7×10 −10 M and 1.5×10 −9 M , respectively. They also displaced [ 3 H]‐BK binding to B 2 receptors in human lung fibroblast IMR‐90 cells, with an IC 50 of 1.6×10 −9 M and 9.8×10 −10 M , respectively. In guinea‐pig isolated ileum‐preparations, FR165649 had no agonistic effect on contraction and caused parallel rightward shifts of the concentration‐response curves to BK on contraction. Analysis 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 induced 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 bradykinin B 2 receptor antagonist, Hoe 140 ( D ‐Arg‐[Hyp 3 , Thi 5 , D ‐Tic 7 , Oic 8 ]BK) in a non‐competitive manner. In IMR‐90 cells, FR165649 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 cells with a pD 2 of 8.4±0.1, and this effect was inhibited by Hoe 140. These results indicate that FR165649 and FR190997 are, respectively, a potent bradykinin B 2 receptor antagonist and agonist, and that the agonistic activity depends on the small part of the nonpeptide ligand. FR165649 and FR190997 may be useful tools for studying the relationship between ligands and receptors.