2. Academic Validation
  3. Searching for Synthetic Opioid Rescue Agents: Identification of a Potent Opioid Agonist with Reduced Respiratory Depression

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

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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