New Class of Drugs May Provide Pain Relief Without Need for Opioids Interview with:
John Traynor, PhD
Edward F Domino Research Professor
Professor and Associate Chair for Research
Department of Pharmacology, Medical School
Professor of Medicinal Chemistry, College of Pharmacy
University of Michigan, Ann Arbor MI

Dr. Traynor What is the background for this study? What are the main findings?

Response: Response: Morphine and related drugs acting at the mu-opioid receptor are the most effective treatment for moderate to severe pain, yet their use is limited by serious on-target side effects including respiratory depression, and physical and psychological dependence that has led to the opioid crisis.  Current opioid drugs are required because our own endogenous pain relieving chemicals, the enkephalins and endorphins opioid peptides, cannot efficiently relieve pain.  

We have discovered a class of drugs (positive allosteric modulators, PAMs) that bind to the mu-opioid receptor to enhance the activity of endogenous opioids.  These “enkephalin amplifiers” afford pain relief in mouse models without the need for morphine-like compounds and do so with a much reduced side-effect profile. What should readers take away from your report?

Response: The work demonstrates that enkephalin amplifiers or PAMs can afford pain relief with reduced side effects, e.g. respiratory depression, and should be further investigated as a new class of safer, strong analgesics. What recommendations do you have for future research as a result of this study?

Response: This report is a very early stage preclinical proof of principle. Much development work is necessary to create more drug-like molecules, to confirm the compounds provide analgesia in other rodent models and in primates; to confirm that the on-target side-effect profile is safe as well as other necessary safety evaluation and toxicology studies. All this is necessary before moving to human clinical trials.  

Disclosures: We are actively developing novel compounds and working closely with the University of Michigan’s Tech Transfer Office to protect IP and explore potential partnering opportunities 


Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects

Ram Kandasamy, Todd M. Hillhouse, Kathryn E. Livingston, Kelsey E.Kochan, Claire Meurice, Shainnel O. Eans, Ming-Hua Li, Andrew D. White, Bernard P. Roques, Jay P. McLaughlin, Susan L. Ingram, Neil T. Burford, Andrew Alt, John R. Traynor

Proceedings of the National Academy of Sciences Apr 2021, 118 (16) e2000017118; DOI:10.1073/pnas.2000017118

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