Bradykinin antagonists with dehydrophenylalanine analogues at position 5

Continuing the studies on structural requirements of bradykinin antagonists, it has been found that analogues with dehydrophenylalanine (ΔPhe) or its ring?substituted analogues (ΔPhe(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 B₂receptor tissues, the analogues with ΔPhe or ΔPhe(X) at position 5, but without any replacement at position 7, seem to represent a new structural type of B₂receptor antagonist. All the analogues investigated act as partial antagonists; they inhibit the bradykinin?induced contraction at low concentrations and act as agonists at higher concentrations. Ring substitutions by methyl groups or iodine reduce both the agonistic and antagonistic activity. Only substitution by fluorine gives a high potency. Incorporation of ΔPhe into different representative antagonists with key modifications at position 7 does not enhance the antagonist activity of the basic structures, with one exception. Only the combination of ΔPhe at position 5 with D Phe at position 7 increases the antagonistic potency on guinea pig ileum by about one order of magnitude. Radio?ligand binding studies indicate the importance of position 5 for the discrimination of B₂receptor subtypes. The binding affinity to the low?affinity binding site (K_L) was not significantly changed by replacement of Phe by ΔPhe. In contrast, ring?methylation of ΔPhe results in clearly reduced binding to K_L. The affinity to the high?affinity binding site (K_H) was almost unchanged by the replacement of Phe in position 5 by ΔPhe, whereas the analogue with 2?methyl?dehydrophenylalanine completely failed to detect the K_H?site. The peptides were synthesized on the Wang?resin according to the Fmoc/Bu^tstrategy using Mtr protection for the side chain of Arg. The dehydrophenylalanine analogues were prepared by a strategy involving PyBop couplings of the dipeptide unit Fmoc?Gly?ΔPhe(X)?OH to resin?bound fragments. © 1998 European Peptide Society and John Wiley & Sons, Ltd.