POTENT PHOTOAFFINITY-LABELED AND IODINATED ANTAGONISTS OF BRADYKININ

Continuing the studies on photoaffinity labelled analogues of the pept ide hormone bradykinin (BK), several labelled antagonists were synthes ized and characterized regarding their biological activities on rat ut erus (RUT) and guinea pig ileum (GPI), The photoreactive amino acid p- benzoyl-phenylalanine (Bpa) was incorporated in potent, iodinated BK a nalogues at positions -2, -1, 0 and 7. The newly synthesized BK antago nists were derived from HOE 140 ([DArg(0), Hyp(3), Thi(5), D-Tic(7), O ic(8)]-BK) or [D-Phe(7)]-BK. Because the application of Bpa requires a n additional group for the introduction of I-125, iodinated tyrosine w as inserted at different positions as a model for radioiodination. Sui table positions for incorporation of tyrosine residues are -1, 0, 3 an d 7, whereas the compound with 3-I-Tyr at position 4 had only a low bi ological 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-Arg(0), Hyp(3), Thi(5), D-Tic(7), Oic(8)]-BK (pA (2) values 8.06 on RUT and 8.15 on GPI) and [Bpa(-1), D-Arg(0), 3-I-Ty r(3), Thi(5), D-Tic(7), Oic(8)]-BK (pA(2) values 7.55 on RUT and 8.07 on GPI) belong to the most active compounds, The incorporation of D-Bp a at position 7 also resulted in potent analogues. The antagonists [3- I-Tyr(-1), D-Arg(0), D-Bpa(7)]-BK (pA(2) on RUT 7.69) and [3-I-Tyr(-1) , D-Arg(0), D-Bpa(7), Oic(8)]-BK (pA(2) on GPI 7.53) are an alternativ e to the N-terminal modified HOE 140 analogues, Compounds with D-Bpa(7 ) act as pure competitive antagonists, whereas the HOE 140 derivatives show a mixed antagonism, The comparison of the results between photoa ffinity labelled agonists and antagonists suggests that modifications in the series of BK antagonists were better tolerated.