Searching for Synthetic Opioid Rescue Agents. 2: Identification of an Ultra-Potent Synthetic Opioid Rescue Agent

  • J Med Chem. 2025 Jun 26;68(12):13057-13074. doi: 10.1021/acs.jmedchem.5c01108.
Jocelyn Martin  1 ,  Edem Onyameh  1  2 ,  Dan Luo  1  2 ,  Joshua W Powell  1  2 ,  Riya R Trivedi  1 ,  Eric J Woloshin  1 ,  Yating Zhang  1 ,  Jakob D Shaykin  3 ,  Emily D Denehy  3 ,  Alexia R Alsum  1 ,  Emily Prantzalos  1 ,  Qianru Jiang  4 ,  Tao Che  4 ,  Warren J Alilain  5  6 ,  Jill R Turner  1 ,  Michael T Bardo  3 ,  Thomas E Prisinzano  1  2
Affiliations
  • 1. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40506, United States.
  • 2. Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40506, United States.
  • 3. Department of Psychology, University of Kentucky, Lexington, Kentucky 40536, United States.
  • 4. Center for Clinical Pharmacology, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
  • 5. Spinal Cord and Brain Injury Research Center (SCoBIRC), College of Medicine, University of Kentucky, Lexington, Kentucky 40536, United States.
  • 6. Department of Neuroscience, University of Kentucky, Lexington, Kentucky 40536, United States.
PMID: 40499097 DOI: 10.1021/acs.jmedchem.5c01108
Abstract

Ultrapotent synthetic opioids (UPSO) have become increasingly prevalent today, from being implicated in a mass casualty event to contaminating illicit drug supply across the country. These UPSOs are different than semisynthetic and naturally derived opioids, in the sense that UPSOs have a much greater ability to cause opioid-induced respiratory depression (OIRD) and wooden chest syndrome (WCS), two medical phenomena that are essential in the lethality of UPS opioids. Here, we report the identification of a potential rescue agent (9) that is more potent than naloxone (NLX) in vitro and fully reverses fentanyl- and carfentanil-induced ventilatory depression and fentanyl-induced vocal cord closure in rats. Unlike naloxone, rescue agent 9 increases minute ventilation above normal in fentanyl- or carfentanil-treated rats and appears to have limited brain penetrance. Targeting peripheral opioid receptors offers a new strategy for reversing OIRD, and 9 offers a lead toward developing such an agent.

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