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 B 2 receptor antagonists, were studied for their functional activities in isolated guinea-pig ileum smooth muscle. These compounds were compared with the conventional peptide bradykinin B 2 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 (p K B 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 (p K B 8.73). The IC 50 values of compounds I and II were 3.56 × 10 − 8 and 6.30 × 10 − 8 M, respectively, while that of icatibant was 5.02 × 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 B 2 receptor antagonists.