Searching for Synthetic Opioid Rescue Agents: Identification of a Potent Opioid Agonist with Reduced Respiratory Depression

  • J Med Chem. 2024 Jun 13;67(11):9173-9193. doi: 10.1021/acs.jmedchem.4c00333.
Loan Y Vu  1 ,  Dan Luo  1  2 ,  Kai Johnson  1 ,  Emily D Denehy  3 ,  Judy C Songrady  1 ,  Jocelyn Martin  3 ,  Riya Trivedi  1 ,  Alexia R Alsum  1 ,  Jakob D Shaykin  3 ,  Chhabi Lal Chaudhary  1  2 ,  Eric J Woloshin  1 ,  Lindsay Kornberger  1 ,  Nazmul Bhuiyan  1  2 ,  Sean Parkin  4 ,  Qianru Jiang  5 ,  Tao Che  5 ,  Warren Alilain  6  7 ,  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. Department of Chemistry, University of Kentucky, Lexington, Kentucky 40506, United States.
  • 5. Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, Missouri 63110, United States.
  • 6. Spinal Cord and Brain Injury Research Center (SCoBIRC), College of Medicine, University of Kentucky, Lexington, Kentucky 40536, United States.
  • 7. Department of Neuroscience, University of Kentucky, Lexington, Kentucky 40536, United States.
PMID: 38810170 DOI: 10.1021/acs.jmedchem.4c00333
Abstract

While in the process of designing more effective synthetic opioid rescue agents, we serendipitously identified a new chemotype of potent synthetic opioid. Here, we report that conformational constraint of a piperazine ring converts a mu Opioid Receptor (MOR) antagonist into a potent MOR agonist. The prototype of the series, which we have termed atoxifent (2), possesses potent in vitro agonist activity. In mice, atoxifent displayed long-lasting antinociception that was reversible with naltrexone. Repeated dosing of atoxifent produced antinociceptive tolerance and a level of withdrawal like that of fentanyl. In rats, while atoxifent produced complete loss of locomotor activity like fentanyl, it failed to produce deep respiratory depression associated with fentanyl-induced lethality. Assessment of brain biodistribution demonstrated ample distribution of atoxifent into the brain with a Tmax of approximately 0.25 h. These results indicate enhanced safety for atoxifent-like molecules compared to fentanyl.

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