Scientists Take Big Step Toward Finding Non-Addictive Pain Killer

August 29, 2018

With the support of the National Institute on Drug Abuse, scientists at Wake Forest School of Medicine have been working to find a safe, non-addictive pain killer to help fight the current opioid crisis in this country. 

And they may have done just that, though in an animal model.

Known as AT-121, the new chemical compound discovered by study co-author Nurulain Zaveri, Ph.D., of Astraea Therapeutics, has dual therapeutic action that suppressed the addictive effects of opioids and produced morphine-like analgesic effects in non-human primates. 

“In our study, we found AT-121 to be safe and non-addictive, as well as an effective pain medication,” said Mei-Chuan Ko, Ph.D., professor of physiology and pharmacology at the School of Medicine, part of Wake Forest Baptist Medical Center. 
“In addition, this compound also was effective at blocking abuse potential of prescription opioids, much like buprenorphine does for heroin, so we hope it could be used to treat pain and opioid abuse.”
The findings are published in the Aug. 29 issue of the journal Science Translational Medicine.  

The main objective of this study was to design and test a chemical compound that would work on both the mu opioid receptor, the main component in the most effective prescription pain killers, and the nociceptin receptor, which blocks the abuse side effects of mu opioids. Current opioid drugs, such as fentanyl and oxycodone, work only on the mu opioid receptor, which also produces unwanted side effects – respiratory depression, abuse potential, increased sensitivity to pain and physical dependence.

In the study, the researchers observed that AT-121 showed the same level of pain relief but at a 100-times lower dose than morphine. At that dose, it also reduced the reinforcing effects of oxycodone, a commonly abused prescription drug.

“The functional profile of AT-121 supports the hypothesis that bifunctional nociceptin and mu opioid receptor agonists may have a wider therapeutic window. Namely, such compounds produce effective pain relief without other opioid side effects such as abuse liability, respiratory depression and itch,” Ko said. “These studies in non-human primates not only document the therapeutic potential of bifunctional nociceptin and mu opioid receptor agonists, but also develop a translational bridge to facilitate treatment design and options for pain and opioid use disorders.”

Next steps include conducting additional preclinical studies to collect more safety data.

The work was supported by grants from the National Institutes of Health, National Institute on Drug Abuse R01DA032568, R01DA027811, R44DA042465, R21DA040104, and R21DA044775, and the U.S. Department of Defense W81XWH-13-2-0045.

Co-authors are: Huiping Ding, Ph.D., Norikazu Kiguchi, Ph.D., Paul W. Czoty, Ph.D., of Wake Forest School of Medicine; Nurulain T. Zaveri ,Ph.D., Dennis Yasuda, B.S., Pankaj R. Daga, Ph.D.,  Willma, E. Polgar, B.S., James J. Lu, B.S., of Astraea Therapeutics, Mountain View, Calif., and Shiroh Kishioka, M.D., Ph.D., Norikazu Kiguchi, Ph.D.,of Wakayama Medical University, Japan. 

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Marguerite Beck, 716-2415