New bradykinin analogues substituted in positions 7 and 8 with sterically restricted 1-aminocyclopentane-1-carboxylic acid

A sterically constrained non-coded amino acid, 1-aminocyclopentane-1-carboxylic acid (Ape), was introduced in position 7 or 8 of the bradykinin (BK) B-2 receptor antagonist, [D-Arg(0), Hyp(3), Thi(5.8), D-Phe(7)]BK, previously synthesized by Stewart's group. This modification is believed to reduce the flexibility of the peptides, thereby forcing the peptide backbone and side chains to adopt specific orientations. Ape substitution was combined with acylation of the N-terminus with 1-adamantaneacetic acid (Aaa). The activity of four new analogues was assayed in isolated rat uterus and in rat blood pressure tests. The results clearly demonstrated that the Ape residue inserted in position 7 led to a reduction of antagonistic properties in the rat uterus assay or even restored the agonism in the blood pressure test, whereas Ape at position 8 enhanced antagonistic potency in both the tests. In both cases, acylation of the N-terminus led to the enhancement of the antagonistic potency. On the basis of these findings, new potent and selective B-2 blockers might be designed. Copyright (c) 2006 European Peptide Society and John Wiley & Sons, Ltd.