Cyclic Glycopeptide Analogs of Endomorphin‑1 Provide Highly Effective Antinociception in Male and Female Mice

James E. Zadina, Lajos Z. Szabo, Fahad Al-Obeidi, Xing Zhang, Leticia Ferreira Nakatani, Chidiebere Ogbu, M. Leandro Heien, Torsten Falk, Mitchell J. Bartlett, Robin Polt

Research output: Contribution to journalArticlepeer-review

Abstract

Opioids acting at the mu opioid receptor (MOR) remain the most effective treatment for moderate to severe pain, but their use is limited by serious side effects. We have shown that a cyclized analog of endomorphin-1 provided pain relief comparable to that of morphine with reduction or absence of several side effects, including abuse liability. Glycosylation can promote penetration of cellular barriers. Here we developed cyclic glycopeptide endomorphin (glycoEM) analogs as drug candidates for potent and long-lasting analgesia. The analogs were assessed in receptor binding and functional assays and for blood−brain barrier penetration by microdialysis and MS. Two of the analogs showed MOR selectivity and more potent and longer lasting antinociception than morphine in male and female mice. Comparable antinociception occurred at A2 doses 5-fold lower (20-fold on a molar basis) than morphine doses. The results support further study of the glycoEMs for clinical application.

Original languageEnglish (US)
Pages (from-to)1731-1740
Number of pages10
JournalACS Medicinal Chemistry Letters
Volume15
Issue number10
DOIs
StatePublished - Oct 10 2024

Keywords

  • Opioid
  • endomorphin analog
  • glycopeptide
  • pain

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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