Design of Analgesic Trivalent Peptides with Low Withdrawal Symptoms: Probing the Antinociceptive Profile of Novel Linear and Cyclic Peptides as Opioid Pan Ligands

Azzurra Stefanucci, Paola Minosi, Stefano Pieretti, Parthasaradhireddy Tanguturi, Gabriella Molnar, Giuseppe Scioli, Lorenza Marinaccio, Alice Della Valle, John M. Streicher, Adriano Mollica

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


The discovery of efficacious and safe analgesics with reduced side effects is the foremost challenge in the pain field. In this work, we report the in vitro and in vivo evaluation of linear and cyclic analogues of biphalin with the aim to complete the series of structural modifications previously applied in the development of opioid peptides incorporating a xylene bridge. Replacement of Tyr1,1′ by Dmt (2,5-dimethyltyrosine) in the linear biphalin analogue AM94 and cyclic analogue MACE4 resulted in two new compounds (namely, MJ2 and MJ5) endowed with improved KOR/MOR/DOR binding affinity. Both compounds showed a strong antinociceptive profile in in vivo models of nociception, allodynia, and hyperalgesia via the tail flick, hot plate, and formalin tests after intracerebroventricular and subcutaneous administration. One of these ligands, MJ2, was also tested in tolerance and dependence studies, exhibiting very little withdrawal symptoms.

Original languageEnglish (US)
Pages (from-to)506-515
Number of pages10
JournalACS Chemical Neuroscience
Issue number3
StatePublished - Feb 1 2023


  • biphalin
  • nociception
  • opioid
  • pan ligands
  • peptides
  • withdrawal

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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