Fentanyl makeover: Core structural redesign could lead to safer pain medications
Modified molecule shows diminished respiratory depression—the leading cause of opioid overdose deaths—while retaining full pain-blocking capability.
February 11, 2026
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.
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