Opioid Antagonists from the Orvinol Series as Potential Reversal Agents for Opioid Overdose

Alexander Disney, Keith M. Olson, Jessica Anand, Amanda Shafer, Sierra Moore, John Traynor, Stephen Husbands

Research output: Contribution to journalArticlepeer-review

Abstract

The opioid crisis continues to claim many lives, with a particular issue being the ready availability and use (whether intentional or accidental) of fentanyl and fentanyl analogues. Fentanyl is both potent and longer-acting than naloxone, the standard of care for overdose reversal, making it especially deadly. Consequently, there is interest in opioid reversal agents that are better able to counter its effects. The orvinol series of ligands are known for their high-affinity binding to opioid receptors and often extended duration of action; generally, compounds on this scaffold show agonist activity at the kappa and the mu-opioid receptor. Diprenorphine is an unusual member of this series being an antagonist at mu and only a partial agonist at kappa-opioid receptors. In this study, an orvinol antagonist, 14, was designed and synthesized that shows no agonist activity in vitro and is at least as good as naloxone at reversing the effects of mu-opioid receptor agonists in vivo.
Original languageEnglish
Pages (from-to)3108-3117
Number of pages10
JournalACS Chemical Neuroscience
Volume13
Issue number21
Early online date12 Oct 2022
DOIs
Publication statusPublished - 2 Nov 2022

Keywords

  • GPCR
  • diprenorphine
  • kappa-opioid antagonist
  • mu-opioid antagonist
  • opioid antagonist
  • opioid overdose

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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