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

Perlikowska, R. and Malfacini, D. and Cerlesi, M. C. and Calo', G. and Piekielna, J. and Tömböly, Csaba (2014) Pharmacological characterization of endomorphin-2-based cyclic pentapeptides with methylated phenylalanine residues. PEPTIDES, 55C. pp. 145-150. ISSN 0196-9781

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Abstract

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 MePhe4-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.

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