Novel subtype-selective nonpeptide bradykinin receptor antagonists FR167344 and FR173657

被引：76

作者：

Aramori, I ^{[1
]}

Zenkoh, J ^{[1
]}

Morikawa, N ^{[1
]}

ODonnell, N ^{[1
]}

Asano, M ^{[1
]}

Nakamura, K ^{[1
]}

Iwami, M ^{[1
]}

Kojo, H ^{[1
]}

Notsu, Y ^{[1
]}

机构：

[1] FUJISAWA PHARMACEUT CO LTD,EXPLORATORY RES LABS,TSUKUBA,IBARAKI 305,JAPAN

来源：

MOLECULAR PHARMACOLOGY | 1997年 / 51卷 / 02期

关键词：

D O I：

10.1124/mol.51.2.171

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

We describe the receptor binding and antagonistic properties of two novel nonpeptide antagonists, FR167344 (3-bromo-8-[2,6-dichloro-3-[N-[(E)-4-(N,N-dimethylcarbamoyl)cinnamidoacetyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine hydrochloride) and FR173657 (8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline), for the human bradykinin receptor subtypes (B-1 and B-2). In competitive experiments using membranes prepared from Chinese hamster ovary cells expressing the bradykinin receptor subtypes, FR167344 and FR173657 showed a high affinity binding to the B-2 receptor with IC50 values of 65 and 8.9 nM, respectively, and no binding affinity for the B-1 receptor. FR167344 and FR173657 inhibited the B-2 receptor-mediated phosphatidylinositol (PI) hydrolysis and produced a concentration-dependent rightward shift in the dose-response curve to bradykinin. This shift was accompanied by a progressive reduction of maximal response. Estimated pA(2) values for the antagonism of bradykinin-induced PI hydrolysis by FR167344 and FR173657 were 8.0 and 9.0, respectively. FR167344 and FR173657 showed no stimulatory effects on PI hydrolysis. Therefore, FR167344 and FR173657 are potent, highly selective, and insurmountable antagonists for the human bradykinin B-2 receptor.

引用

页码：171 / 176

页数：6

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