title: Pharmacological characterization of endomorphin-2-based cyclic pentapeptides with methylated phenylalanine residues.
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 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.
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Perlikowska
authors.affiliation: Department of Medical Science, Section of Pharmacology and Italian Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Malfacini
authors.affiliation: Department of Medical Science, Section of Pharmacology and Italian Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Maria Camilla
authors.initials: MC
authors.lastname: Cerlesi
authors.affiliation: Department of Medical Science, Section of Pharmacology and Italian Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calo'
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Piekielna
authors.affiliation: Service Commun d'Analyse Comportementale (SCAC), Institut de Recherche et d'Innovation Biomédicale (IRIB), Faculté de Médecine et Pharmacie, Université de Rouen, 76183 Rouen Cedex, France.
authors.forename: Léonore
authors.initials: L
authors.lastname: Floriot
authors.affiliation: Service Commun d'Analyse Comportementale (SCAC), Institut de Recherche et d'Innovation Biomédicale (IRIB), Faculté de Médecine et Pharmacie, Université de Rouen, 76183 Rouen Cedex, France.
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Henry
authors.affiliation: Service Commun d'Analyse Comportementale (SCAC), Institut de Recherche et d'Innovation Biomédicale (IRIB), Faculté de Médecine et Pharmacie, Université de Rouen, 76183 Rouen Cedex, France; Centre National de la Recherche Scientifique (CNRS), France.
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: do-Rego
authors.affiliation: Institute of Biochemistry, Biological Research Centre of Hungarian Academy of Sciences, 6701 Szeged, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Tömböly
authors.affiliation: Faculty of Chemistry, University of Wroclaw, 50-383 Wroclaw, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Kluczyk
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland. Electronic address: anna.janecka@umed.lodz.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D011485:Protein Binding; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C105294:endomorphin 2; D010649:Phenylalanine; C067359:4-methylphenylalanine
keywords: Calcium mobilization; Cyclic peptides; Hot-plate test; Opioid receptors; Receptor binding; Solid phase peptide synthesis