부산대학교 도서관

A number of biologically active peptides including bradykinin (BK) are known to elicit an unspecific, non-receptor-mediated release of mediators from mast cells. We have investigated whether novel, nonpeptide BK B2receptor ligands, i.e., the antagonists N-[N-[3-[(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yl)oxymethyl]-2,4-dichlorophenyl]-N-methylaminocarbonylmethyl]-4-(dimethylaminocarbonyl)cinnamylamide hydrochloride (FR167344) and (E)-3-(6-acetamido-3-pyridyl)-N-[N-(2,4-dichloro-3-{(2-methyl-8-quinolinyl)oxymethyl}phenyl]-N-methylaminocarbonylmethyl]acrylamide (FR173657), and the agonist 8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (FR190997), would be devoid of this unspecific action. Paw oedema in anaesthetized rats was observed following subplantar injection of BK, FR190997, the B2antagonist d-Arg-[Hyp3, Thi5, d-Tic7, Oic8]-BK (icatibant, previously Hoe-140), the B1agonist des-Arg9-BK (DABK) and the B1antagonist des-Arg9-[Leu8]-BK (DALBK). The effect of BK was inhibited by systemic pretreatments with icatibant and methysergide in an additive manner, whereas the local effect of icatibant was only sensitive to methysergide. Oedema induced by DABK and DALBK was also attenuated by methysergide. Mepyramine pretreatment was ineffective for all oedema-producing agents. Effects of FR190997 were abolished by pretreatment with icatibant. FR167344 and FR173657 did not induce oedema formation. Depletion of mast cells by compound 48/80 mimicked the effects of methysergide on BK and icatibant and had no effect on FR190997. It is concluded that the novel nonpeptide receptor ligands are devoid of the unspecific mast cell-degranulating action observed with the peptide ligands.