Redoubling the ring size of an endomorphin-2 analog transforms a centrally acting mu-opioid receptor agonist into a pure peripheral analgesic

Justyna Piekielna, Rossella De Marco, Luca Gentilucci, Maria Camilla Cerlesi, Girolamo Calo', C. Tömböly, Roberto Artali, Anna Janecka

Research output: Contribution to journalArticle

4 Citations (Scopus)


The study reports the synthesis and biological evaluation of two opioid analogs, a monomer and a dimer, obtained as products of the solid-phase, side-chain to side-chain cyclization of the pentapeptide Tyr-d-Lys-Phe-Phe-AspNH2. The binding affinities to the mu, delta, and kappa opioid receptors, as well as results obtained in a calcium mobilization functional assay are reported. Tyr-[d-Lys-Phe-Phe-Asp]2-NH2 1 was a potent and selective full agonist of mu with sub-nanomolar affinity, while the dimer (Tyr-[d-Lys-Phe-Phe-Asp]2-NH2)2 2 showed a significant mixed mu/kappa affinity, acting as an agonist at the mu. Molecular docking computations were utilized to explain the ability of the dimeric cyclopeptide 2 to interact with the receptor. Interestingly, in spite of the increased ring size, the higher flexibility allowed 2 to fold and fit into the mu receptor binding pocket. Both cyclopeptides were shown to elicit strong antinociceptive activity after intraventricular injection but only cyclomonomer 1 was able to cross the blood–brain barrier. However, the cyclodimer 2 displayed a potent peripheral antinociceptive activity in a mouse model of visceral inflammatory pain.

Original languageEnglish
Pages (from-to)309-317
Number of pages9
Publication statusPublished - May 1 2016



  • calcium mobilization
  • cyclization of peptides
  • molecular docking
  • opioid receptors
  • receptor binding

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Biomaterials
  • Organic Chemistry

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