Synthesis of biologically active retroenantiomers of angiotensin peptides

The effect of the reversal of the direction of amide bonds in the peptide chain of angiotensin was determined by the synthesis and study of retroenantiomers of the following peptides: 1 [Val5]angiotensin II (angiotensin); 2, [Suc1]angiotensin (desamino-angiotensin); 3, [Ala7]desamino-angiotensin; 4, [beta-Ala7]desamino-angiotensin. In all of these retroenantiomers, the N-terminal Phe residue was replaced by a benzylmalonyl moiety in order to maintain the topological features of angiotensin's C terminus which are important for biological activity. The separation of the diasteromeric peptides containing D- or L-benzylmalonyl residues was possible in the cases of the retroenantiomers of 1 and 2 but not in those of 3 and 4. The retroenantiomers of 1 and 2 were devoid of smooth muscle contracting activities, while those of 3 and 4 contracted the isolated guinea-pig ileum and rat uterus with activities ranging from 8 to 24%, when compared with the respective parent compounds. The results indicate that (a) the sense of the peptide bonds in angiotensin's backbone is not essential for activity, and (b) the Pro7 residue in angiotensin is important for maintaining an "active" conformation of the molecule. The compounds reported in this paper are the first retroenantiomers of linear peptide hormones that have been shown to retain the biological activities of the parent compounds.