Bradykinin antagonists: synthesis and in vitro activity of bissuccinimidoalkane peptide dimers.

A systematic study on dimerization of the bradykinin (BK) antagonist D-Arg0-Arg1-Pro2-Hyp3-Gly4-Phe5-Ser6-D-Phe 7-Leu8-Arg9 has been performed. Several of the dimeric BK antagonists displayed remarkable activities and long durations of action. Rank order of antagonist potency as a function of dimerization position is as follows: rat uterus 6 > 5 > 0 > 2 > 1 > 3 >> 4,7,8,9; guinea pig ileum 6 > 5 > 3 > 2 > 1 > 0 >> 4,7,8,9. These results suggest that the development of BK antagonists of significant therapeutic potential may be possible using a dimerization strategy that can overcome the heretofore limiting problems of potency and in vivo duration of action.