AT₂-Selective Angiotensin II Analogues Containing Tyrosine-Functionalized 5,5-Bicyclic Thiazabicycloalkane Dipeptide Mimetics

Abstract

This paper reports the synthesis of two angiotensin II analogues with tyrosine-functionalized 5,5-bicyclic thiazabicycloalkane dipeptide mimetics replacing the Tyr(4)-Ile(5) residues. The preparation of these analogues relies on the synthesis and incorporation of an alpha,alpha-disubstituted chimeric amino acid derivative and on-resin bicyclization to a cysteine residue. The synthesized analogues both displayed high angiotensin AT(2)/AT(1) receptor binding preferences and had AT(2) receptor affinities in the same low nanomolar range as angiotensin II itself. Conformational analysis, using experimental constraints derived from NMR studies, indicated that the Tyr(4) and His(6) residues in one of the angiotensin II analogues were in close proximity to each other.

A Single β-Amino Acid Substitution to Angiotensin II Confers AT 2 Receptor Selectivity and Vascular Function

“…30 In other studies, analogs with tyrosine-functionalized bicyclic dipeptides replacing the Tyr 4 -Ile 5 residues presented an extended backbone conformation with heightened AT 2 R-to-AT 1 R selectivity. 31 The majority of the aforementioned studies relied on binding affinity estimates derived from displacement of iodinated Ang II from AT 1 R in rat liver membranes and AT 2 R in pig uterine membranes. However, functional assays on Ang II peptidomimetics that would indicate agonist or antagonist cardiovascular activity are lacking.…”

AT2 receptors: Functional relevance in cardiovascular disease

“…Initially, a nonpeptide agonist for both AT 1 R and AT 2 R was identified (Wan et al, 2004a) and this was soon followed by the first selective non-peptide AT 2 R agonist, Compound 21, which was active in 2 in vivo bioassays where it enhanced alkaline secretion from rat intestine and lowered BP in anaesthetized SHR (Wan et al, 2004b). In addition, a number of other peptide-based AT 2 R mimetics have been made by the same research group following extensive structure-activity relationships using Ang II or analogues (Johannesson et al, 2004;Georgsson et al, 2005;Rosenstrom et al, 2005;Georgsson et al, 2006). More recently, new peptide-based ligands have been designed that may become lead compounds for future drug development (Georgsson et al, 2007).…”

Modeling binding modes of angiotensin II and pseudopeptide analogues to the AT2 receptor

“…The binding conformation of Ang II when interacting with the AT 2 receptor has been investigated to a lesser extent, but monoand bi-cyclizations, including turn mimicking structures, in the 3-5 region of Ang II have produced analogues with retained affinity [7,[17][18][19][20][21]. An extended receptor-bound conformation of Ang II has also been suggested in the case of AT 2 binding [16].…”