New bradykinin Analogues Substituted in Positions 6 and 7 with Enantiomers of N-Methylphenylalanine

Four new analogues of a previously designed bradykinin antagonist, D-Arg-Arg-Pro--Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg, containing replacements in positions 6 and 7 with all possible combinations of enantiomers of N-methylphenylalanine (MePhe) were designed, synthesized and bioassayed. The presence of two consecutive MePhe residues in the sequence of the analogues caused great difficulties in the synthesis. The best results for the CO-N(CH 3 ) bond formation were obtained using O-(7-azabenzotriazol-1-yl)-1,1,3,3--tetramethyluronium hexafluorophosphate/7-azabenzotriazol-1-ol (HATU/HOAt) as coupling reagent (Fmoc strategy). The antagonistic potency of these peptides was assessed by their ability to inhibit vasodepressor response to exogenous bradykinin in conscious rats. Our results showed that the modifications proposed resulted in a decrease in antagonistic activity. However, we demonstrated once again that the D-amino acid in position 7 of BK antagonists may be replaced by a suitable L-amino acid residue. Our results may be of value in the design of new B 2 -antagonists.