Opioid drugs provide people with relief from debilitating pain but come with dangers: risk of addiction, unpleasant withdrawal symptoms, and potentially fatal overdose. In a study published in ACS Central Science, scientists have identified a strategy for designing safer opioids. They demonstrated that an experimental opioid, which binds to an unconventional site on the receptor, suppresses pain in animal models with fewer side effects, particularly those associated with fatal overdoses.

Opioid drugs exploit the body's natural pain relief system by activating opioid receptors on nerve cells in the brain. Although these drugs are meant to help people, they can sometimes cause harm. People taking opioids can become physically dependent on them, where sudden discontinuation can trigger withdrawal symptoms, such as muscle aches, nausea, and vomiting. Additionally, opioids slow and shallow breathing, a side effect that can be fatal.

Attempts to design safer opioids have mainly focused on identifying molecules that bind to the same site on the receptor, known as the active site, where natural pain-relief signals bind. In earlier research, scientists found a molecule called C6 guano, which can activate the opioid receptor when it binds outside the active site. C6 guano interacts with a location within the opioid receptor that usually responds to sodium ions. Despite promising effects, C6 guano has a significant drawback: it cannot cross the blood-brain barrier that protects the organ. Therefore, a team led by Susruta Majumdar, Jay McLaughlin, Haoqing Wang, and Ruth Huttenhain set out to improve this discovery by identifying a similar molecule with the potential to travel from the bloodstream to the opioid receptors in the brain.

To find an alternative that also binds to the opioid receptor, researchers synthesized and evaluated 10 compounds with chemistry that could allow passage through the blood-brain barrier. During initial testing in cells, they identified the most promising candidate derived from fentanyl, called RO76. By capturing molecules near the activated receptor, the team showed that RO76 produces a signal within cells that is different from those triggered by classical opioids, such as morphine.

They then assessed the compound's efficacy in mice. In these experiments, RO76 seemed as effective as morphine in suppressing pain. But when comparing the opioids' effects on the animals' breathing rate, they found that RO76 slows breathing much less, suggesting it may not be as deadly as morphine. Likewise, when mice were given an opioid-blocking drug, those chronically taking RO76 experienced fewer withdrawal symptoms than those taking morphine. Moreover, the team found that, when administered orally, the new fentanyl derivative has similar, though somewhat lower, pain-suppressing effects compared to injection under the skin of animals. Researchers say these results suggest that RO76 has the potential for development as an oral medication for humans.

One of the key steps in researching safer opioids is identifying molecules that can cross the blood-brain barrier. This barrier is a protective layer of cells that prevents many substances from entering the brain, thus ensuring the stability of the brain's internal environment. Identifying compounds that can cross this barrier presents a significant challenge in pharmacology.

In recent research, a team of scientists from the University of Washington's Center for Clinical Pharmacology, led by Susruta Majumdar, conducted detailed tests of the compound RO76 on animal models. The results showed that RO76 can significantly reduce pain without causing severe side effects like respiratory depression, which is common with traditional opioids. Additionally, the compound showed a lower potential for causing addiction compared to morphine.

Funding for this research was provided by the National Institutes of Health and the Pharmaceutical Research and Manufacturers of America through postdoctoral fellowships. Two authors also acknowledged financial interests related to biopharmaceutical companies. These results represent a significant advancement in the research of safer opioids and offer the potential for developing new drugs that can provide effective pain relief with minimal risk of severe side effects.

Source: American Chemical Society