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Kam YL, Ro JY, Kim HJ, Choo HY: Antagonistic effects of novel non-peptide chlorobenzhydryl piperazine compounds on contractile response to bradykinin in the guinea-pig ileum. Eur J Pharmacol. 2005 Oct 31;523(1-3):143-50. Epub 2005 Oct 13.
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. |
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