As part of our continuing studies on the structure–activity relationships of cyclic pentapeptides based onthe structure of endomorphin-2, we report here the synthesis and biological activities of a new series ofanalogs incorporating 2, 3or 4-methylphenylalanine (MePhe) residues into positions 3 or 4 of the par-ent cyclopeptide, Dmt-c[d-Lys-Phe-Phe-Asp]NH2(Dmt = 2,6-dimethyltyrosine). Analogs with MePhe inposition 4 showed a row of magnitude increased -opioid receptor (MOP receptor) affinity as comparedwith a parent compound. The in vitro potencies of the new analogs were determined in calcium mobi-lization assay performed in Chinese Hamster Ovary (CHO) cells expressing human recombinant opioidreceptors and chimeric G proteins. All analogs were strong / (MOP/KOP) receptor agonists and weak (DOP) receptor agonists. In the in vivo hot-plate test in mice, the MePhe4-modified peptides showedremarkable antinociceptive activity after intracerebroventricular (i.c.v.) administration which was mostlikely due to the concomitant activation of more than one opioid receptor type.
Pharmacological characterization of endomorphin-2-based cyclic pentapeptides with methylated phenylalanine residues
MALFACINI, Davide;CERLESI, Maria Camilla;CALO', Girolamo;
2014
Abstract
As part of our continuing studies on the structure–activity relationships of cyclic pentapeptides based onthe structure of endomorphin-2, we report here the synthesis and biological activities of a new series ofanalogs incorporating 2, 3or 4-methylphenylalanine (MePhe) residues into positions 3 or 4 of the par-ent cyclopeptide, Dmt-c[d-Lys-Phe-Phe-Asp]NH2(Dmt = 2,6-dimethyltyrosine). Analogs with MePhe inposition 4 showed a row of magnitude increased -opioid receptor (MOP receptor) affinity as comparedwith a parent compound. The in vitro potencies of the new analogs were determined in calcium mobi-lization assay performed in Chinese Hamster Ovary (CHO) cells expressing human recombinant opioidreceptors and chimeric G proteins. All analogs were strong / (MOP/KOP) receptor agonists and weak (DOP) receptor agonists. In the in vivo hot-plate test in mice, the MePhe4-modified peptides showedremarkable antinociceptive activity after intracerebroventricular (i.c.v.) administration which was mostlikely due to the concomitant activation of more than one opioid receptor type.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
