Structure-Based Design of Glycosylated Oxytocin Analogues with Improved Selectivity and Antinociceptive Activity

Lajos Z. Szabó, Parthasaradhireddy Tanguturi, Hannah J. Goodman, Sára Sprőber, Chenxi Liu, Fahad Al-Obeidi, Mitchell J. Bartlett, Torsten Falk, Vlad K. Kumirov, M. Leandro Heien, John M. Streicher, Robin Polt

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Acute and chronic pain is often treated with opioids despite the negative side effects of constipation, physical dependence, respiratory depression, and overdose. The misuse of opioid analgesics has given rise to the opioid crisis/epidemic, and alternate nonaddictive analgesics are urgently needed. Oxytocin, a pituitary hormone, is an alternative to the small molecule treatments available and has been used as an analgesic as well as for the treatment and prevention of opioid use disorder (OUD). Clinical implementation is limited by its poor pharmacokinetic profile, a result of the labile disulfide bond between two cysteine residues in the native sequence. Stable brain penetrant oxytocin analogues have been synthesized by replacement of the disulfide bond with a stable lactam and glycosidation of the C-terminus. These analogues show exquisite selectivity for the oxytocin receptor and potent in vivo antinociception in mice following peripheral (i.v.) administration, supporting further study of their clinical potential.

Original languageEnglish (US)
Pages (from-to)163-170
Number of pages8
JournalACS Medicinal Chemistry Letters
Volume14
Issue number2
DOIs
StatePublished - Feb 9 2023

Keywords

  • cyclic
  • glycopeptide
  • neurohormone
  • oxytocin agonist
  • pain

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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