Pharmacological characterization of a nonpeptide bradykinin B2 receptor antagonist, FR165649, and agonist, FR190997.
1. The nonpeptide bradykinin (BK) B2 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-pyridyl methoxy)quinoline) have been identified. These compounds have a common chemical structure, and the 2-pyridylmethoxy group is the only structural difference between them. 2. Both FR165649 and FR190997 displaced [3H]-BK binding to B2 receptors in guinea-pig ileum membranes, with an IC50 of 4.7 x 10(-10) M and 1.5 x 10(-9) M, respectively. They also displaced [3H]-BK binding to B2 receptors in human lung fibroblast IMR-90 cells, with an IC50 of 1.6 x 10(-9) M and 9.8 x 10(-10) M, respectively. 3. 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 pA2 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 pD2 of 7.9+/-0.2 and the contraction was inhibited by a specific peptide bradykinin B2 receptor antagonist, Hoe 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]BK) in a non-competitive manner. 4. 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 pD2 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 B2 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.
Asano
M
M
Department of Pharmacology, Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
Hatori
C
C
Sawai
H
H
Johki
S
S
Inamura
N
N
Kayakiri
H
H
Satoh
S
S
Abe
Y
Y
Inoue
T
T
Sawada
Y
Y
Mizutani
T
T
Oku
T
T
Nakahara
K
K
D000818:Animals; D065168:Bradykinin Receptor Antagonists; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D006868:Hydrolysis; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010716:Phosphatidylinositols / Q000378:metabolism; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology*; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000819:agonists* / Q000378:metabolism
D065168:Bradykinin Receptor Antagonists; C114162:FR 165649; C107104:FR 190997; D010716:Phosphatidylinositols; D011804:Quinolines; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin