title: Antagonistic effects of novel non-peptide chlorobenzhydryl piperazine compounds on contractile response to bradykinin in the guinea-pig ileum.
abstract: Two novel compounds, N-phenylacetyl-N'-(4-methoxybenzyl)-N''-1-(4-chlorobenzhydryl)piperazine iminodiacetic acid triamide (compound I) and N-phenylacetyl-N'-(4-methylbenzyl)-N''-1-(4-chlorobenzhydryl)piperazine iminodiacetic acid triamide (compound II), designed and synthesized as novel non-peptide bradykinin B2 receptor antagonists, were studied for their functional activities in isolated guinea-pig ileum smooth muscle. These compounds were compared with the conventional peptide bradykinin B2 receptor antagonist, icatibant (H-DArg-Arg-Pro-Hyp-Gly-Thi-Ser-dTic-Oic-Arg-OH) for their in vitro functional activities. Compounds I and II showed highly potent, time-dependent insurmountable antagonism against contractile responses to bradykinin (pKB 8.80 and 8.57, respectively) with progressive reduction of maximum effect maintaining the concentration producing half maximal-response unchanged. Otherwise, icatibant, known as a non-competitive antagonist, showed a rightward displacement of cumulative concentration-response curves to bradykinin with decrease of its maximum effect (pKB 8.73). The IC50 values of compounds I and II were 3.56 x 10(-8) and 6.30 x 10(-8) M, respectively, while that of icatibant was 5.02 x 10(-8) M. The profile of action of compounds I and II varied when contact time was prolonged from 5 to 60 min, whereas that of icatibant did not. The inhibitory effects of the newly synthesized compounds and icatibant on the contractile response to bradykinin were differently reverted by washout (icatibant < 100 min, compounds I and II > 100 min). This class of compounds containing the chlorobenzhydryl piperazine moiety is expected to be a novel non-peptide bradykinin B2 receptor antagonists.
authors.affiliation: School of Pharmacy, Ewha Womans University, Seoul, 120-750, South Korea.
authors.forename: Yoo Lim
authors.initials: YL
authors.lastname: Kam
authors.forename: Jai Youl
authors.initials: JY
authors.lastname: Ro
authors.forename: Hwa-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Hea-Young Park
authors.initials: HY
authors.lastname: Choo
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects*; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D043782:Receptor, Bradykinin B2 / Q000187:drug effects*
chemical_list: D010879:Piperazines; D043782:Receptor, Bradykinin B2; C065679:icatibant; D001920:Bradykinin