Synthesis, resolution, and assignment of configuration of potent hypotensive retro-inverso bradykinin potentiating peptide 5a(BPP5a) analogues

The effect on the biological activity of an inverted amide group as an isosteric replacement for the Phe-Ala scissile bond of the BPP5a analogue [Phe3]BPP5a has been studied. The synthesis of the retroinverso pentapeptide [gPhe3,(R,S)-mAla4]BPP5a has been carried out in solution by coupling the pseudopeptide epimer HO-(R,S)-mAla-Pro-OBut to Glp-Lys(Boc)-gPhe-H·HCl, separation and identification of the resulting diastereoisomers [Lys2(Boc),gPhe3,(S)-mAla4,Pro5-OBut]BPP5a and [Lys2(Boc),gPhe3,(R)-mAla4,Pro5-OBut]BPP5a, and finally acidolytic cleavage. [gPhe3,(S)-mAla4]BPP5a, a moderate inhibitor of angiotensin converting enzyme (ACE)in vitro(I50= 14 × 10–5M), was obtained and proved to be more potent than BPP5a as a hypotensive in normotensive rats without manifesting the bradykinin potentiating action of the natural peptide.