Pharmacological characterization of endomorphin-2-based cyclic pentapeptides with methylated phenylalanine residues

As part of our continuing studies on the structure-activity relationships of cyclic pentapeptides based on the structure of endomorphin-2, we report here the synthesis and biological activities of a new series of analogs incorporating 2', 3' or 4'-methylphenylalanine (MePhe) residues into positions 3 or 4 of the parent cyclopeptide, Dmt-c[D-Lys-Phe-Phe-Asp]NH2 (Dmt = 2',6'-dimethyltyrosine). Analogs with MePhe in position 4 showed a row of magnitude increased mu-opioid receptor (MOP receptor) affinity as compared with a parent compound. The in vitro potencies of the new analogs were determined in calcium mobilization assay performed in Chinese Hamster Ovary (CHO) cells expressing human recombinant opioid receptors and chimeric G proteins. All analogs were strong mu/kappa (MOP/KOP) receptor agonists and weak delta (DOP) receptor agonists. In the in vivo hot-plate test in mice, the MePhe(4)-modified peptides showed remarkable antinociceptive activity after intracerebroventricular (i.c.v.) administration which was most likely due to the concomitant activation of more than one opioid receptor type. (C) 2014 Elsevier Inc. All rights reserved.