Potent photoaffinity labelled and iodinated antagonists of bradykinin

Continuing the studies on photoaffinity labelled analogues of the peptide hormone bradykinin (BK), several labelled antagonists were synthesized and characterized regarding their biological activities on rat uterus (RUT) and guinea pig ileum (GPI). The photoreactive amino acid p-benzoyl-phenylalanine (Bpa) was incorporated in potent, iodinated BK analogues at positions -2, -1, 0 and 7. The newly synthesized BK antagonists were derived from HOE 140 ([DArg0, Hyp3, Thi5, D-Tic7, Oic8]-BK) or [D-Phe7]-BK. Because the application of Bpa requires an additional group for the introduction of 125I, iodinated tyrosine was inserted at different positions as a model for radioiodination. Suitable positions for incorporation of tyrosine residues are -1, 0, 3 and 7, whereas the compound with 3-I-Tyr at position 4 had only a low biological activity. The antagonists obtained by modification of HOE 140 generally retained a high antagonistic potency. In this group [D-Bpa-2, 3-I-D-Tyr-1, D-Arg0, Hyp3, Thi5, D-Tic7, Oic8]-BK (pA2 values 8.06 on RUT and 8.15 on GPI) and [Bpa-1, D-Arg0, 3-I-Tyr3, Thi5, D-Tic7, Oic8]-BK (pA2 values 7.55 on RUT and 8.07 on GPI) belong to the most active compounds. The incorporation of D-Bpa at position 7 also resulted in potent analogues. The antagonists [3-I-Tyr-1, D-Arg0, D-Bpa7]-BK (pA2 on RUT 7.69) and [3-I-Tyr-1, D-Arg0, D-Bpa7, Oic8]-BK (pA2 on GPI 7.53) are an alternative to the N-terminal modified HOE 140 analogues. Compounds with D-Bpa7 act as pure competitive antagonists, whereas the HOE 140 derivatives show a mixed antagonism. The comparison of the results between photoaffinity labelled agonists and antagonists suggests that modifications in the series of BK antagonists were better tolerated.