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Synthesis of mixed MOR/KOR efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration.
Perlikowska, Renata; Piekielna, Justyna; Gentilucci, Luca; De Marco, Rossella; Cerlesi, Maria Camilla; Calo, Girolamo; Artali, Roberto; Tömböly, Csaba; Kluczyk, Alicja; Janecka, Anna.
Afiliación
  • Perlikowska R; Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, 92-215, Lodz, Poland.
  • Piekielna J; Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, 92-215, Lodz, Poland.
  • Gentilucci L; Department of Chemistry, University of Bologna, Via Selmi 2, 40126, Bologna, Italy.
  • De Marco R; Department of Chemistry, University of Bologna, Via Selmi 2, 40126, Bologna, Italy.
  • Cerlesi MC; Department of Medical Science, Section of Pharmacology and Italian Institute of Neuroscience, University of Ferrara, 44121, Ferrara, Italy.
  • Calo G; Department of Medical Science, Section of Pharmacology and Italian Institute of Neuroscience, University of Ferrara, 44121, Ferrara, Italy.
  • Artali R; Scientia Advice, di Roberto Artali, 20832, Desio, Monza and Brianza, Italy.
  • Tömböly C; Institute of Biochemistry, Biological Research Centre of Hungarian Academy of Sciences, 6701, Szeged, Hungary.
  • Kluczyk A; Faculty of Chemistry, University of Wroclaw, 50-383, Wroclaw, Poland.
  • Janecka A; Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, 92-215, Lodz, Poland. Electronic address: anna.janecka@umed.lodz.pl.
Eur J Med Chem ; 109: 276-86, 2016 Feb 15.
Article en En | MEDLINE | ID: mdl-26785295
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligopéptidos / Receptores Opioides kappa / Receptores Opioides mu / Analgésicos Opioides Límite: Animals Idioma: En Revista: Eur J Med Chem Año: 2016 Tipo del documento: Article País de afiliación: Polonia Pais de publicación: Francia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligopéptidos / Receptores Opioides kappa / Receptores Opioides mu / Analgésicos Opioides Límite: Animals Idioma: En Revista: Eur J Med Chem Año: 2016 Tipo del documento: Article País de afiliación: Polonia Pais de publicación: Francia