Can Fentanyl Be ‘Rewired’ to Make It Safer?

By Pat Anson

Scientists at Scripps Research have found a way to change fentanyl’s molecular structure to reduce the risk of overdosing, while at the same time preserving its pain-relieving properties. 

The findings, published in the ACS Medicinal Chemistry Letters, suggest that next-generation synthetic opioids could have less risk of addiction, respiratory depression, and death. 

Fentanyl has been used safely and effectively for over 50 years as a surgical analgesic, and by patients with severe pain from cancer and other intractable pain conditions. Only in the past decade has illicit fentanyl emerged as a potent and deadly street drug that fueled the U.S. overdose crisis.

That has given fentanyl a bad name – and led to efforts to “rewire” fentanyl and other opioids to make them safer, but still effective as pain relievers.

“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 Janda, PhD, Professor of Chemistry at the Skaggs Institute For Chemical Biology. 

“Our research has identified a different possibility—that fundamental structural redesign can preserve pain relief while improving safety.”

Janda and his colleagues used a medicinal chemistry strategy known as “bioisosteric replacement,” a method used to redesign molecules to have different effects than the original molecules. 

To engineer the change in fentanyl, scientists replaced the central ring structure of fentanyl molecules with an entirely different one called “2-azaspiro[3.3]heptane.” The new compound doesn’t bind as much to nerve receptors in the brain that regulate breathing. 

When the redesigned fentanyl was tested on laboratory mice, the team arrived at a dose that remained effective as an analgesic, while the mice “appeared normal with no indication of distress or signs of acute toxicity.” 

Slowed breathing in the mice occurred only at very high doses and was temporary, with breathing returning to normal within 25-30 minutes. The new analog has a short half-life of about 27 minutes – the amount of time it takes for the liver to metabolize and break down the drug. Other medicines have a long half-life of several hours or even days — which makes them potentially more toxic.

“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.

The research appears promising and may someday benefit pain patients, but it overlooks the fact that illicit fentanyl is involved in most overdoses. The drug cartels and street dealers that sell it will have little interest in changing the chemical structure of illicit fentanyl to make it safer.