Effects of a nonpeptide bradykinin B2 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 asthma. 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 B2 receptor antagonist, FR167344 (N-[N-[3-[(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yl)oxymethyl]-2 ,4-dichlorophenyl]-N-methylaminocarbonylmethyl]-4-(dimethylamin ocarbonyl)cinnamylamide hydrochloride), on guinea-pig tracheal smooth muscle bradykinin receptors. FR167344 inhibited [3H]bradykinin binding to bradykinin receptors in epithelium-denuded guinea-pig tracheal membrane with an IC50 of 2.1 nM and a Ki of 0.44 nM. This compound also inhibited bradykinin-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 trachea even at 10(-6) M. These results indicate that FR167344 has the specific antagonistic activity against guinea-pig tracheal smooth muscle bradykinin receptors.
Asano
M
M
Department of Pharmacology, Fujisawa Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
Sawai
H
H
Hatori
C
C
Inamura
N
N
Fujiwara
T
T
Nakahara
K
K
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000378:metabolism; D014132:Trachea / Q000187:drug effects* / Q000502:physiology; D014316:Tritium
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D065168:Bradykinin Receptor Antagonists; C106745:FR 167344; D011725:Pyridines; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D014316:Tritium; C051090:bradykinin, Leu(8)-des-Arg(9)-; C065679:icatibant; D002217:Carbachol; C053010:NPC 567; D001920:Bradykinin