Synthesis, biological activity and resistance to proteolytic digestion of new cyclic dermorphin/deltorphin analogues

A series of novel cyclic ureidopeptides, analogues of dermorphine/deltorphine tetrapeptide, were synthesized by solid phase peptide synthesis and/or in solution. The antinociceptive activity of N-substituted amides 1–10 was evaluated using hot-plate and tail-flick tests. Analogue 1 showed significant, stronger than morphine, antinociceptive effect after systemic applications. All analogues were also tested for their in vitro resistance to proteolysis by means of mass spectroscopy and it was found that all substituted amides 1–10 showed full stability during incubation with large excess of chymotrypsin and pepsin. Compound 1 is a lead molecule for further evaluation. [Display omitted] ► Novel cyclic ureidopeptides analogues of dermorphin/deltorphin were synthesized. ► Their in vivo antinociceptive activity and resistance to proteolysis were evaluated. ► N-substituted amides with D-amino acid showed extremely high proteolytic stability. ► Analogue 1 showed significant antinociceptive effect after systemic applications.