LA JOLLA, CA—Fentanyl is one of the most effective drugs for managing severe pain, yet it carries substantial risks of addiction and respiratory depression, the dangerous and sometimes fatal slowed breathing. These safety concerns have limited the use of the drug despite how well it works. Meanwhile, the ease and low cost of manufacturing have enabled widespread illegal production, fueling an overdose epidemic that claimed more than 70,000 U.S. lives in 2023.
Now, chemists at Scripps Research have modified fentanyl's molecular structure to develop a version that reduces respiratory depression while fully preserving its pain-relieving properties. The findings, published in the ACS Medicinal Chemistry Letters on January 22, 2026, suggest that future modifications could yield next-generation opioid therapies that carry less risk of addiction, overdose and death. This paper was also recognized in the " ACS Editor's Choice ," a collection of publications selected by scientific editors of ACS journals from around the world.
"For decades, the pharmaceutical industry has been constrained by the assumption that major structural changes to opioids would eliminate their analgesic properties," says senior author Kim D. Janda , the Ely R. Callaway Jr. Professor of Chemistry at Scripps Research. "Our research has identified a different possibility—that fundamental structural redesign can preserve pain relief while improving safety."
Synthetic opioids like fentanyl occupy a complex position in medicine. Initially promoted as breakthrough medications with minimal addiction risk (claims that have proven tragically false), they remain essential for managing severe acute pain despite their significant dangers.
In this study, Janda used a medicinal chemistry strategy known as "bioisosteric replacement," which is often used to redesign molecules to have similar, but improved qualities when compared to the original counterparts. To engineer this improvement, the team replaced the central ring structure with an entirely different geometry: a structure called 2-azaspiro[3.3]heptane, which looks like the links of paper chains.
This "spirocyclic" shape of 2-azaspiro[3.3]heptane consists of two small, four-sided rings that are connected at a single point, representing a dramatic departure from the original construction.
"Rather than tweaking small parts of the molecule, we replaced the entire central structure with something that looks completely different in three-dimensional space," says first author Arran Stewart, a research associate in the Janda laboratory.
Despite this significant structural shift, the bioisosteric replacement of fentanyl's central core was remarkably effective in blocking pain. The team attributes this to its binding affinity, or how tightly a drug attaches to its target receptors. Opioid drugs, specifically, attach to their target receptors through an electrical attraction between a positively charged part of the drug and a negatively charged amino acid inside the receptor's binding pocket. This critical anchor point allows the receptor to recognize and respond to the drug. The structural redesign preserves this essential anchor while changing many of the other molecular contacts, maintaining enough receptor activation to produce pain relief even though it has a different overall binding pattern than fentanyl.
Notably, the new compound showed no detectable recruitment of the beta-arrestin pathway, a cellular signaling corridor that scientists believe contributes to respiratory depression and other dangerous side effects. The research indicated that slowed breathing occurred only at very high doses and was temporary, with breathing returning to normal within 25-30 minutes. The analog also left the body quickly, with a half-life of approximately 27 minutes—a short-acting profile that could be beneficial in controlled medical settings.
This retooling of the fentanyl scaffold is a new chemical addendum in Janda's broader strategy to address opioid overdose and adverse effects. The team plans to leverage this discovery to develop new opioid patent-free vaccines that train the immune system to recognize and neutralize fentanyl molecules before they reach the brain.
"Finding ways to preserve the analgesic properties of the synthetic opioids without encumbering the perils of respiratory depression could help derisk the toxicity associated with synthetic opioid use while providing a new conduit for pain management," says Janda.
In addition to Janda and Stewart, authors of the study, " Fentanyl-Rewired: A 2-Azaspiro[3.3]heptane Core Preserves μ-Opioid Function ," include Lisa Eubanks and Mingliang Lin of Scripps Research.
This work was supported by the Shadek Family Foundation.
About Scripps Research
Scripps Research is an independent, nonprofit biomedical research institute ranked one of the most influential in the world for its impact on innovation by Nature Index. We are advancing human health through profound discoveries that address pressing medical concerns around the globe. Our drug discovery and development division, Calibr-Skaggs, works hand-in-hand with scientists across disciplines to bring new medicines to patients as quickly and efficiently as possible, while teams at Scripps Research Translational Institute harness genomics, digital medicine and cutting-edge informatics to understand individual health and render more effective healthcare. Scripps Research also trains the next generation of leading scientists at our Skaggs Graduate School, consistently named among the top 10 US programs for chemistry and biological sciences. Learn more at www.scripps.edu .
