Influence of C-Terminal Modifications of Bradykinin Antagonists on Their Activity

In the present study we have described the synthesis and some pharmacological properties of four new analogues of bradykinin (BK). Two peptides were designed by substitution of positions 7 and 8 of known B2 antagonists with N-methyl-L-phenylalanine [Phe(Me)]. The next two analogues were obtained by replacement of D-Phe residue in position 7 of known B2 antagonist with 1-naphthyl-D-alanine or 2-naphthyl-D-alanine. The antagonistic potency of peptides was assessed by their ability to inhibit vasodepressor response to exogenous bradykinin in conscious rats. Although our studies demonstrated disadvantegous influence of Phe(Me)7,8 modification for B2 antagonism, we showed that D-amino acid residue in position 7 of BK antagonists may be replaced by suitable L-amino acid residue. As regards (D-Nal)7 substitution, we found strikingly different antagonistic potencies of analogues which differ only in the presence of D-1-Nal and D-2-Nal. We assume that it is due to different conformations of these peptides, proving the importance of the shape of the C-terminal part of B2 antagonists for their activity.