A study led by researchers at WashU Medicine and the University of Health Sciences and Pharmacy in St. Louis (UHSP) has revealed a promising new path for pain relief that avoids the severe side effects associated with traditional opioids. The study, published in Nature Communications on March 13, 2025, introduces C6-Quino, a compound designed to target the delta opioid receptor (δOR) rather than the traditional mu opioid receptor (µOR), which is activated by opioids such as morphine and fentanyl.
The research team, led by Susruta Majumdar, PhD, and Tao Che, PhD, aimed to overcome challenges seen in earlier δOR therapies, particularly their link to seizures. However, the new compound, C6-Quino, acts as a partial agonist, meaning it activates the receptor just enough to relieve pain, without triggering harmful effects like respiratory depression or seizures—making it a safer alternative for treating chronic pain.
“The opioid crisis continues to devastate communities across the nation, and the quest for safer pain management is more urgent than ever,” said Majumdar, professor of anesthesiology. “C6-Quino could provide a breakthrough in chronic pain treatment.”
The study’s co-authors include Balazs Varga, PhD, a senior scientist in the Majumdar Lab, and Sarah Bernhard, a pre-doctoral trainee in the Division of Biology & Biomedical Sciences at WashU Medicine. Bernhard is also a member of both the Majumdar Lab and the Che Lab. Together, they contributed to the development and testing of C6-Quino. The team used advanced techniques to study the structure of δOR and found that C6-Quino interacts with a specific part of the receptor called the sodium binding pocket. This interaction allows the drug to partially activate the receptor, which helps reduce side effects while still providing strong pain relief.
“The timing of this discovery could not be more crucial. The opioid crisis demands innovative solutions, and the potential of C6-Quino as a safer, non-addictive pain medication aligns with public health priorities. While further research is needed to translate these findings into clinical practice, the study paves the way for a new class of pain relievers that mitigate the risks of overdose and addiction,” said Che, associate professor of anesthesiology.
Studies showed that C6-Quino activates pain-relief signals without overactivating pathways that cause many opioid-related side effects. The drug demonstrated effective pain relief in preclinical chronic pain models—like migraine, neuropathic and inflammatory pain—setting it apart from other analgesics. As the team continues to explore the therapeutic potential of C6-Quino and similar compounds, their work represents a critical step toward more responsible and effective pain treatment. By promoting safer pain management strategies, they aim to improve the quality of life for people with chronic pain while helping curb the broader opioid crisis.
Funded by the National Institute of Drug Abuse (R01DA057790), this work is a collaboration with Vsevolod Katritch, PhD, at the University of Southern California, and Jay P. Mclaughlin, PhD, at the University of Florida.