Bradykinin analogs containing α-aminoisobutyric acid (Aib)

doi:10.1016/0196-9781(80)90059-5

Peptides

Volume 1, Issue 3, Autumn 1980, Pages 231-235

https://doi.org/10.1016/0196-9781(80)90059-5 Get rights and content

Abstract

All seven possible bradykinin (BK) analogs containing Aib in place of proline have been synthesized by the solid phase method and assayed for in vitro myotropic activity on the guinea pig ileum and rat uterus, and in vivo on the rat blood pressure, both by intravenous and intra-aortic administration. [Aib^2,3]-BK, [Aib^2,7]-BK, and [Aib^2,3,7]-BK had no in vivo or in vitro activities; [Aib²]-BK, [Aib³]-BK and [Aib^3,7]-BK had moderate BK-like activities and a significantly increased resistance to pulmonary inactivation in the rat ([Aib^3,7]-BK was totally resistant). [Aib⁷]-BK was found to be the most active position seven BK analog yet assayed on the rat blood pressure, and shows remarkably high ileum (4 times BK) and intravenous rat blood pressure (6 times BK) activity.

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Practical bradykinin antagonists were discovered in 1984 by Vavrek and Stewart and reported in “Peptides.” At that time there was already much evidence for involvement of bradykinin in inflammation and pain, so the specific, competitive antagonists were widely accepted and applied. The key to conversion of bradykinin into an antagonist was replacement of the proline residue at position 7 with a d-aromatic amino acid. Other modifications converted the initial weak antagonists into modern peptides which are totally resistant to all degrading enzymes, are orally available, and have been used in clinical trials. Non-peptide bradykinin antagonists have also been developed.
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Kinins contribute to the acute inflammatory response and are implicated in the pathophysiology of inflammatory disease. The development of therapeutically viable agents that counteract the effects of kinins is, therefore, potentially very rewarding. Since kinin actions are generally mediated via an interaction with cell-surface receptors, one approach is the development of site-specific receptor antagonists. The emphasis in this review is to outline our current understanding of the properties of bradykinin receptors and the potential therapeutic applications for drugs acting at these sites. As a result of the recent introduction of potent bradykinin receptor antagonists and the cloning of bradykinin receptor genes, considerable advances in kinin research can now be confidently anticipated.
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The use of NMR methods to study conformational and dynamic aspects of the proline residues in the nonapeptide bradykinin is reviewed. NMR analyses involve considerations of bistable equilibria which include the cis/trans conformational heterogeneity of the imide bond, the cis'/trans' regions of conformational stability which characterize rotation about the C_α—CO bond (dihedral angle Ψ), and the interconversion of the pyrrolidine ring of proline between puckered C_γ-endo and C_γ-exo conformations. These conformational features are all characterized by different kinetic behavior, are interdependent with peptide bond conformation, and exhibit sensitivity to amino acid substitutions. Thus, the substitution of Gly⁶ for Ser⁶ increases the fractional cis probability of the sixth peptide bond from 0.1 to 0.35. Substitutions of α-aminoisobutyric acid (AIB) residues for proline introduce conformational constraints analogous to those in cis' proline. Correlations of pyrrolidine ring conformation and dynamics with the cis/trans ratio of the imide bond have also been observed in model systems. Conformational and activity analyses of [AIB⁷]-bradykinin provided a stimulus for the development of the first bradykinin antagonist by Stewart and Vavrek (Vavrek RJ and Stewart JM, Competitive antagonists of bradykinin. Peptides6: 161–164, 1985).
Studies on the hydrocarboxylation of N-acetylimines, enamines and allylamines.
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Bradykinin analogs containing α-aminoisobutyric acid (Aib)

Abstract

Biochem. Biophys. Acta

J. biol. Chem.

Biochem. Biophys. Acta

Analyt. Biochem.

Tetrahedron

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Acta

Interaction of α-chymotrypsin with several α-methyl-α-acylamino acid methyl esters

Biochemistry

Optical enantiomorphs of isovaline

J. Am. chem. Soc.

An obligatory α-helical amino acid residue

Biopolymers

A circular dichroism study of the secondary structure of bradykinin

Biochemistry

The hydrolytic action of acylase-l on N-acyl amino acids

J. Am. chem. Soc.

Drugs which antagonize 5-hydroxytryptamine

Br. J. Pharmac.

Synthesis of a 19-residue peptide with alamethicin-like activity

A new t-butoxycarbonyl reagent, 2-t-butoxycarbonylimino-2-phenylacetonitrile

Tetrahedron Lett.

Peptides 17. Synthesis of peptides and polymers of some sterically hindered amino acids via oxazolone intermediates

J. chem. Soc.

Angiotensin-II analogs. 7. Stereochemical factors in the 5 position influencing pressor activity

J. med. Chem.