New bradykinin analogues acylated on the N-terminus: effect on rat uterus and blood pressure.

Our previous studies suggested that acylation of the N-terminus of several known B2 antagonists with various kinds of bulky acyl groups consistently improved their antagonistic potency in rat blood pressure assay. On the other hand, our earlier observations also seemed to suggest that the effects of acylation on the contractility of isolated rat uterus depended substantially on the chemical character of the acyl group, as we observed that this modification might either change the range of antagonism or even transform it into agonism. Bearing all this in mind, we decided to synthesize seven new analogues of bradykinin by N-terminal acylation with various acyl groups of a moderately potent B2 antagonist, previously synthesized by Stewart's group, D-Arg-Arg-Pro-Hyp-Gly-Thr-Ser-D-Phe-Thi-Arg.

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 (Apc), 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. Apc substitution was combined with acylation of the N-terminus with 1-adamantaneacetic acid (Aaa).

New bradykinin analogues modified in the C-terminal part with sterically restricted 1-aminocyclohexane-1-carboxylic acid.

In the present work, a sterically constrained noncoded amino acid, 1-aminocyclohexane-1-carboxylic acid (Acc), was substituted in position 8 of the peptide chain of bradykinin (BK) and position 6, 7, or 8 of its B2 receptor antagonist [D-Arg0,Hyp3,Thi,(5,8)D-Phe7]BK, previously synthesized by Stewart's group, to reduce the flexibility of the peptides, thus forcing the peptide backbone and side chains to adopt specific orientations. Knowing that acylation of the N-terminus of several known B2 blockers with a variety of bulky groups has consistently improved their antagonistic potency in the rat blood pressure assay, the Acc substituted analogues were also synthesized in the N-acylated form with 1-adamantaneacetic acid (Aaa). The activity of eight new analogues was assayed in isolated rat uterus and in rat blood pressure tests.