Researchers identify strategy for designing safer opioids

Opioid drugs offer people relief from debilitating pain, but these drugs carry risks: the risk of addiction, miserable withdrawal symptoms, and the potential for fatal overdose. In a study in ACS Central Science, researchers have identified a strategy for designing safer opioids. They showed that an experimental opioid, which binds to an unconventional site on the receptor, suppresses pain in animal models with fewer side effects -? especially those associated with fatal overdoses.

Opioid drugs enter the body’s natural pain-relieving system by activating pain-suppressing opioid receptors on nerve cells in the brain. Although medicines are meant to help people, sometimes these medicines lead to harm. People who take opioids can become physically dependent on them, where sudden cessation can cause withdrawal symptoms such as muscle pain, nausea and vomiting. Additionally, opioids make breathing slow and shallow, a side effect that can be fatal.

Efforts to design safer opioids have largely focused on identifying molecules that bind to the same spot on the receptor, known as the active site, where the body’s own pain signals attach. In a previous study, researchers found a molecule called C6 guano, which can activate the opioid receptor when it binds outside the active site. C6 guano interacts with a site within the opioid receptor that normally responds to sodium ions. Despite its promising results, C6 guano has a major drawback: It cannot pass through the blood-brain barrier that protects the organ. So a team led by Susruta Majumdar, Jay McLaughlin, Haoqing Wang and Ruth Huttenhain set out to improve on this discovery by identifying a similar molecule with the ability to travel from the bloodstream to opioid receptors in the brain.

To find an alternative that also binds to the opioid receptor, the researchers synthesized and evaluated 10 compounds with chemistry that could allow passage through the blood-brain barrier. In their initial testing on cells, they identified the most promising candidate derived from fentanyl, called RO76. By trapping molecules near the activated receptor, the team showed that RO76 produces a signal inside cells that differs from those initiated by classic opioids, such as morphine.

They then evaluated the compound’s effectiveness in mice. In these experiments, RO76 appeared to suppress pain as effectively as morphine. But when they compared the effects of opioids on the animals’ breathing rates, they found that RO76 slowed breathing much less, suggesting it may not be as lethal as morphine. Similarly, when mice were given an opioid blocking drug, mice chronically given RO76 showed fewer withdrawal symptoms than those given morphine. In addition, the team found that, when given orally, the new fentanyl derivative had similar, though slightly lower, pain-relieving effects than when it was injected under the animals’ skin. The researchers say these results suggest that RO76 has the potential to be developed as an oral drug for humans.