TY - JOUR T1 - Novel Subtype-Selective Nonpeptide Bradykinin Receptor Antagonists FR167344 and FR173657 JF - Molecular Pharmacology JO - Mol Pharmacol SP - 171 LP - 176 DO - 10.1124/mol.51.2.171 VL - 51 IS - 2 AU - Ichiro Aramori AU - Junko Zenkoh AU - Noriyuki Morikawa AU - Nuala O’Donnell AU - Masayuki Asano AU - Kozo Nakamura AU - Morita Iwami AU - Hitoshi Kojo AU - Yoshitada Notsu Y1 - 1997/02/01 UR - http://molpharm.aspetjournals.org/content/51/2/171.abstract N2 - 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 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 B2 receptor. ER -