Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9921055 | European Journal of Pharmacology | 2005 | 8 Pages |
Abstract
Two novel compounds, N-phenylacetyl-Nâ²-(4-methoxybenzyl)-Nâ³-1-(4-chlorobenzhydryl)piperazine iminodiacetic acid triamide (compound I) and N-phenylacetyl-Nâ²-(4-methylbenzyl)-Nâ³-1-(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 Ã 10â 8 and 6.30 Ã 10â 8 M, respectively, while that of icatibant was 5.02 Ã 10â 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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Authors
Yoo Lim Kam, Jai Youl Ro, Hwa-Jung Kim, Hea-Young Park Choo,