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

Abstract

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). The activity of four new analogues was assayed in isolated rat uterus and in rat blood pressure tests. The results clearly demonstrated that the Apc 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 Apc 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.

Novel Bradykinin Analogues Modified in the N-Terminal Part of the Molecule with a Variety of Acyl Substituents

“…Male Wistar rats were maintained on a regular chow diet and tap water at ambient temperature (22 ± 1°C). The assay was based on the previously published procedure (Labudda-Dawidowska et al 2005; Labudda et al 2006, 2007) with minor modifications. Handling of the experimental animals was done under supervision of the local Ethics Committee of the Medical University of Gdańsk.…”

Solution and fluorous phase synthesis of β,β-difluorinated 1-amino-1-cyclopentane carboxylic acid derivatives

“…By means of the general procedure previously described [10], 8c was obtained from 7b (610 mg) as a yellow oil (344 mg) in 54% yield after flash chromatography with toluene:dichloromethane (4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heptadecafluoroundecyl)-dimethylsily])ethyl 3,3-difluoro-2-(4-methoxyphenylimino)-5-phenylpent-4-enoate (14) By means of the general procedure previously described [10], 14 was obtained from 8a (1.05 g) as a yellow oil (645 mg) in 30% yield after fluorous solid-phase extraction. 1 By means of the general procedure previously described [4], 9a was obtained from 8a (35 mg) as a colorless oil (37 mg) in 92% yield after flash chromatography with hexane:ethyl acetate (20:1) as eluent, previously deactivated with a solution of n-hexane/Et 3 N 2%.…”

“…Indeed, this type of unit has recently been incorporated into the peptidic chain of bradikynin, resulting in new analogues that show reduced antagonistic properties [5]. In the same vein, a similar derivative was included in the structure of peptidomimetics to afford effective inhibitors of cathepsin K [6].…”

B2 bradykinin receptor antagonists: adsorption mechanism on electrochemically roughened Ag substrate

“…1‐aminocyclohexane‐1‐carboxylic acid, at position 7. Until recently, the presence of an aromatic D‐amino acid residue in position 7 was considered necessary for B 2 antagonism …”

“…Despite the enormous interest in BK and its anatagonists, there is limited information about these peptide structures and the observed changes in BK receptor binding upon peptide chain modification. These areas must be clarified to increase our understanding of the interaction mechanism between BK and the B 2 receptor.…”