Effect of potent endomorphin degradation blockers on analgesic and antidepressant-like responses in mice

The biological effects of endomorphins (EMs) are short-lasting due to their rapid degradation by endogenous enzymes. Competing enzymatic degradation is an approach to prolong EM bioavailability. In the present study, a series of tetra- and tripeptides of similar to EMs structure was synthesized and tested in vitro and in vivo for their ability to inhibit degradation of EMs. The obtained results indicated that, among the series of analogs, the tetrapeptide Tyr–Pro–d–ClPhe–Phe–NH2 and the tripeptide Tyr–Pro–Ala–NH2, which did not bind to the μ-opioid receptors, were potent inhibitors of EM catabolism in rat brain homogenate. In vivo, these two peptides significantly prolonged the analgesic and antidepressant-like effects, induced by exogenous EMs, by blocking EM degrading enzymes. These new potent inhibitors may therefore increase the level and the half life of endogenous EMs and could be used in a new therapeutic strategy against pain and mood disorders, based on increasing of EM bioavailability. ► In this study, we developed and synthesized a series of endomorphin degradation blockers. ► We demonstrated that the novel inhibitors of EM-degrading enzymes prolong EM analgesic and antidepressant-like effects. ► These inhibitors might become potential candidates for lead compounds in a new therapeutic strategy against pain and mood disorders.