title: Antinociceptive and antidepressant-like action of endomorphin-2 analogs with proline surrogates in position 2.
abstract: In our efforts to develop new candidate drugs with antinociceptive and/or antidepressant-like activity, two novel endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2) analogs, containing proline surrogates in position 2 were synthesized using commercially available racemic trans-4-phenylpyrrolidine-3-carboxylic acid (4-Ph-β-Pro). The obtained mixture of two diastereoisomeric peptides (2a and 2b) was separated by HPLC and both enantiopure analogs were used in the in vitro and in vivo studies. To assign the absolute configuration to the 4-Ph-β-Pro residues in both peptides, the stereoselective synthesis of (3R,4S)-4-phenylpyrrolidine-3-carboxylic acid was performed and this enantiomer was introduced into position 2 of EM-2 sequence. Based on the HPLC retention times we were able to assign the absolute configuration of 4-Ph-β-Pro residues in both peptide analogs. Analog 2a incorporating (3R,4S)-4-Ph-β-Pro residue produced strong analgesia in mice after intracerebroventricular (icv) administration which was antagonized by the μ-opioid receptor (MOR) antagonist, β-funaltrexamine (β-FNA). This analog also influenced an emotion-related behavior of mice, decreasing immobility time in the forced swimming and tail suspension tests, without affecting locomotor activity. The antidepressant-like effect was reversed by the δ-selective antagonist, naltrindole (NLT) and κ-selective nor-binaltorphimine (nor-BNI). Thus, the experiments with selective opioid receptor antagonists revealed that analgesic action of analog 2a was mediated through the MOR, while the δ- and κ-receptors (DOR and KOR, respectively) were engaged in the antidepressant-like activity. Analog 2b with (3S,4R)-4-Ph-β-Pro in position 2 showed no antinociceptive or antidepressant-like activity in animal studies.
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Perlikowska
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Piekielna
authors.affiliation: TriMen Chemicals Ltd, 92-318 Lodz, Poland.
authors.forename: Marzena
authors.initials: M
authors.lastname: Mazur
authors.affiliation: TriMen Chemicals Ltd, 92-318 Lodz, Poland.
authors.forename: Robert
authors.initials: R
authors.lastname: Koralewski
authors.affiliation: TriMen Chemicals Ltd, 92-318 Lodz, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Olczak
authors.affiliation: Service Commun d'Analyse Comportementale (SCAC), IRIB, Faculté de Médecine et Pharmacie, Université de Rouen, 76183 Rouen Cedex, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: do Rego
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, 90-924 Lodz, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Modranka
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, 90-924 Lodz, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Janecki
authors.affiliation: Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland. Electronic address: anna.janecka@umed.lodz.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D003863:Depression / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011392:Proline / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship; D013550:Swimming
chemical_list: D000700:Analgesics; D000928:Antidepressive Agents; D009842:Oligopeptides; D011957:Receptors, Opioid; C105294:endomorphin 2; D011392:Proline
keywords: Binding studies; Forced-swimming test; Hot-plate test; Locomotor activity; Opioid receptors; Tail-suspension test; Unnatural amino acids