Synthesis and analytical profile of new synthetic analogs of angiotensin 1-7, the main balancing peptide of the renin–angiotensin system

Abstract

The heptapeptide angiotensin Asp-Arg-Val-Tyr-Ile-His-Pro (ANG 1-7) is a key member of the ACE2/ANG-(1-7)/MasR axis, which is considered a counter-regulator of the classical renin–angiotensin system (RAS) axis concerning its homeostatic and neuromodulatory functions. Four new analogs of ANG 1-7 with general structures of Asp-Arg-Val-Tyr-Ile-His-Xxx-NH₂, where Xxx is 1-aminocyclopentanecarboxylic acid (Ac5c), 1-aminocyclohexane carboxylic acid (Ac6c), and (2S,4S)-4-amino-pyrrolidine-2-carboxylic acid, were synthesized and characterized by electrochemical, spectral, DFT calculational, and behavioral methods. The presence of a cis-oriented primary amino group at the molecule's C-terminus is coupled with the structural rigidity of the pyrrolidine Pro ring in the peptide molecule ANG-P1. While in ANG-P2, the cis-oriented primary amino group is connected to the peptide motif by means of the amino acid His leading to the formation of a proline/GABA cis-chimera. The partition coefficient values suggest better lipophilicity of the compounds ANG-P1 and ANG-P2 related to easier passage through the target membranes. The correlation coefficient between the theoretically predicted and experimentally determined logP values is 0.991. The ANG-P1 analog has features comparable to ANG 1-7, but the peptides ANG-P2, ANG-C5, and ANG-C6 exhibit distinct effects, particularly on anxiety-like behavior, according to a comparison of the novel analogs with the precursor peptide. Regardless of how they affect exploration in the open field test, they induce anxiogenic behavior in the elevated plus maze test. The ANG-C5 analog differs from the other analogs because it is unable to create antinociception, despite the fact that ANG 1-7 and its analogs generated notable antinociception.