• Renata Perlikowska, Davide Malfacini, Maria Camilla Cerlesi, Girolamo Calo', Justyna Piekielna, Léonore Floriot, Tiphaine Henry, Jean Claude do-Rego, Csaba Tömböly, Alicja Kluczyk, and Anna Janecka.
• Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland.
• Peptides. 2014 May 1; 55: 145-50.

AbstractAs 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 μ-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 μ/κ (MOP/KOP) receptor agonists and weak δ (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. Copyright © 2014 Elsevier Inc. All rights reserved.

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