Safer opioids in mice with a sideways approach

Opioids are some of the oldest known treatments for pain relief, but they can cause serious side effects. A team of researchers including Susruta Majumdar, a medicinal chemist and pharmacologist at Washington University in St. Louis, has designed an opioid that latches on to receptors in the brain by homing in on water molecules at a key position (ACS Cent. Sci. 2024, DOI: 10.1021/acscentsci.4c00525). The small molecule relieved pain in mice while also appearing to have fewer dangerous side effects than morphine.

Opioids relieve pain by binding to opioid receptors in the brain. Once attached, the drugs trigger a cascade of biological processes that alleviate pain. Scientists have previously found that opioids with lower efficacy than drugs like fentanyl and morphine are still powerful enough to provide pain relief, and they’re potentially safer. Buprenorphine is one such compound that is used to treat people with opioid use disorder.

Majumdar’s group wanted to make an opioid with lower efficacy than fentanyl. The researchers hoped their approach could complement scientists’ efforts to find safer ways to relieve pain given the opioid overdose epidemic.

The team had previously designed an opioid that binds to the mu opioid receptor’s active site as well as an allosteric sodium site outside the receptor’s active site. But that compound struggled to penetrate the blood-brain barrier. This time around, the researchers opted to target the sodium site via water molecules. The resulting opioid, which researchers named RO76, forms hydrogen bonds with the water molecules, which in turn bind to the sodium site.

“It’s really interesting, the way that [they’re] able to probe and interact with different parts of the receptor,” says John Streicher, a pain neuropharmacologist at the University of Arizona who was not involved in the research. “That is remarkable.”

Compared with mice treated with morphine, mice treated with RO76 showed similar signs of pain relief but fewer withdrawal symptoms and reduced respiratory depression—the slow and shallow breathing that leads to overdose deaths.

Majumdar believes that scientists can use similar water-binding approaches to design additional safer opioids.

“There are waters throughout the opioid receptor that can be used,” he says. “With advances in structural biology and [cryogenic electron microscopy] coming to the fore of drug discovery, I’m hoping more people in the G protein–coupled receptor field will look over this concept.”