title: Synthesis of mixed MOR/KOR efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration.
abstract: Cyclic pentapeptide Tyr-c[D-Lys-Phe-Phe-Asp]NH2, based on the structure of endomorphin-2 (EM-2), which shows high affinity to the μ-opioid receptor (MOR) and a very strong antinociceptive activity in mice was used as a parent compound for the structure-activity relationship studies. In this report we synthesized analogs of a general sequence Dmt-c[D-Lys-Xaa-Yaa-Asp]NH2, with D-1- or D-2-naphthyl-3-alanine (D-1-Nal or D-2-Nal) in positions 3 or 4. In our earlier papers we have indicated that replacing a phenylalanine residue by the more extended aromatic system of naphthylalanines may result in increased bioactivities of linear analogs. The data obtained here showed that only cyclopeptides modified in position 4 retained the sub-nanomolar MOR and nanomolar κ-opioid receptor (KOR) affinity, similar but not better than that of a parent cyclopeptide. In the in vivo mouse hot-plate test, the most potent analog, Dmt-c[D-Lys-Phe-D-1-Nal-Asp]NH2, exhibited higher than EM-2 but slightly lower than the cyclic parent peptide antinociceptive activity after peripheral (ip) and also central administration (icv). Conformational analyses in a biomimetic environment and molecular docking studies disclosed the structural determinants responsible for the different pharmacological profiles of position 3- versus position 4-modified analogs.
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 Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, 92-215, Lodz, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Piekielna
authors.affiliation: Department of Chemistry, University of Bologna, Via Selmi 2, 40126, Bologna, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Gentilucci
authors.affiliation: Department of Chemistry, University of Bologna, Via Selmi 2, 40126, Bologna, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: De Marco
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: Scientia Advice, di Roberto Artali, 20832, Desio, Monza and Brianza, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Artali
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: D000595:Amino Acid Sequence; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D009842:Oligopeptides; D010456:Peptides, Cyclic; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C105294:endomorphin 2
keywords: Antinociception; Binding studies; Calcium mobilization assay; Conformational analysis; Endomorphins; Hot-plate test; Molecular docking; ROESY