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Molecular Biological Research Laboratory (I.A., J.Z., N.M., N.O.,
K.N., M.I., H.K., Y.N.) and
Exploratory Research Laboratories
(M.A.), Fujisawa Pharmaceutical Co., Ltd., Tsukuba 300-26, Japan
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 (B1 and
B2). 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
B2 receptor with IC50 values of 65 and 8.9 nM, respectively, and no binding affinity for the
B1 receptor. FR167344 and FR173657 inhibited the
B2 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
pA2 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
B2 receptor.
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