Effects of a nonpeptide bradykinin B-2 receptor antagonist, FR167344, on guinea-pig tracheal smooth muscle bradykinin receptors

It is speculated that bradykinin may play an important role in asthma. Thus , bradykinin receptor antagonists may have therapeutic potential against as thma. Orally active bradykinin antagonists would be more desirable for the treatment of the disease. In the present study, we examined the effects of a novel, potent, selective, and orally active nonpeptide bradykinin B-2 rec eptor antagonist, FR167344 (N-[N-[3-[(3-bromo-2-methylimidazo[1,2-a]pyridin -8-yl)oxymethyl]-2,4-dichlorophenyl]-N-methylaminocarbonylmethyl]-4-(dimeth ylaminocarbonyl)cinnamylamide hydrochloride), on guinea-pig tracheal smooth muscle bradykinin receptors. FR167344 inhibited [H-3]bradykinin binding to bradykinin receptors in epithelium-denuded guinea-pig tracheal membrane wi th an IC50 of 2.1 nM and a K-i of 0.44 nM. This compound also inhibited bra dykinin-induced contraction of epithelium-denuded guinea-pig trachea with a pK(B) of 10.8, but had no effect on carbachol-induced contraction of the t rachea even at 10(-6) M. These results indicate that FR167344 has the speci fic antagonistic activity against guinea-pig tracheal smooth muscle bradyki nin receptors.