Ac-D-Trp-PheNH2 AND Ac-D-Trp-Phe-GlyNH2 - A NEW CLASS OF UNUSUAL OPIOID PEPTIDES

In the last few years we discovered and investigated novel cyclic opioid peptides, c[Tyr-Xaa-D-Trp- Phe-Yaa], based on the sequence of EM-1. These peptides, deprived of a protonable amino group, bind and activate the MOR receptor mainly through the side chains of the amino acids 2 and 3, as revealed by molecular docking analysis. As a consequence, we synthesized and tested short di- and tri-peptides containing the sequence D-Trp- Phe, aiming to determine the minimal requisites necessary for the pharmacological effect. This study lead to the new linear peptides Ac-D-Trp-PheNH2 and Ac-D-Trp-Phe-GlyNH2, which revealed a good affinity for MOR, and agonist efficacy in vivo. Substitution of D-Trp with other amino acids gave inactive compounds or moderate antagonism. Conformational analysis and docking suggested that the short peptides adopt a bioactive conformation characterized by a beta-turn.