BRADYKININ ANTAGONISTS WITH DEHYDROPHENYLALANINE ANALOGS AT POSITION-5

Continuing the studies on structural requirements of bradykinin antago nists, it has been found that analogues with dehydrophenylalanine (Del ta Phe) or its ring-substituted analogues (Delta Phe(X)) at position 5 act as antagonists on guinea pig pulmonary artery, and on guinea pig ileum. Because both organs are considered to be bradykinin B-2 recepto r tissues, the analogues with Delta Phe or Delta Phe(X) at position 5, but without any replacement at position 7, seem to represent a new st ructural type of B-2 receptor antagonist. All the analogues investigat ed act as partial antagonists; they inhibit the bradykinin-induced con traction at low concentrations and act as agonists at higher concentra tions. Ring substitutions by methyl groups or iodine reduce both the a gonistic and antagonistic activity. Only substitution by fluorine give s a high potency. Incorporation of Delta Phe into different representa tive antagonists with key modifications at position 7 does not enhance the antagonist activity of the basic structures, with one exception. Only the combination of Delta Phe at position 5 with DPhe at position 7 increases the antagonistic potency on guinea pig ileum by about one order of magnitude. Radio-ligand binding studies indicate the importan ce of position 5 for the discrimination of B-2 receptor subtypes. The binding affinity to the low-affinity binding site (K-L) was not signif icantly changed by replacement of Phe by Delta Phe. In contrast, ring- methylation of Delta Phe results in clearly reduced binding to K-L. Th e affinity to the high-affinity binding site (K-H) was almost unchange d by the replacement of Phe in position 5 by Delta Phe, whereas the an alogue with 2-methyl-dehydrophenylalanine completely failed to detect the K-H-site. The peptides were synthesized on the Wang-resin accordin g to the Fmoc/Bu-t strategy using Mtr protection for the side chain of Arg. The dehydrophenylalanine analogues were prepared by a strategy i nvolving PyBop couplings of the dipeptide unit Fmoc-Gly-Delta PheN-OH to resin-bound fragments. (C) 1998 European Peptide Society and John W iley & Sons, Ltd.