A drug strategy abandoned after causing tremors, seizures and death in animals has been revived with a redesign that makes the compound less “sticky” — allowing it to let go faster from its target in the spinal cord. In mice, the new version relieved neuropathic pain without the dangerous side effects that derailed earlier attempts, potentially opening a new path beyond opioids for chronic nerve pain.
Imagine if a cool breeze on your cheek felt like a jolt of electricity, or if putting on a pair of sandals felt like walking on hot coals. For millions of people with neuropathy, damaged nerves scramble the body’s pain signals so badly that the nervous system begins misreading ordinary sensations as threats.
“Things that normally shouldn’t hurt — touch, heat or cold — suddenly become painful,” says Azadeh Shahsavar, an associate professor and researcher in drug design and pharmacology at the University of Copenhagen.
Neuropathy can result from a pinched nerve, as with sciatica, one of the world’s most commonly diagnosed pain conditions; from chronic diseases such as diabetes; or as a side effect of treatments including radiation for cancer. Yet roughly half of patients get little or no meaningful relief from the frontline drugs used to treat neuropathic pain.
But new research, published in Nature Communications, presents a drug candidate designed to interrupt pain signalling in a far more targeted way — directly in the spinal cord. Early tests in mice suggest the compound may avoid many of the side effects that limit existing neuropathy drugs, including drowsiness and sedation.
“We’re on the verge of hopefully identifying something that could be effective at treating neuropathic pain, without relying on opioids,” says Chris Cioffi, a coauthor of the new study and professor and medicinal chemist at Rensselaer Polytechnic Institute.
Sticky drugs and the spinal cord’s pain highway
Pregabalin, originally developed to treat epilepsy, has become the frontline treatment for neuropathic pain. “Lyrica - the brand name of pregabalin - is one of the top-selling drugs of all time,” Cioffi says. But many patients get little meaningful relief from the drug, which works by dampening the hyperactive nerve signalling that develops after nerve injury.
If pregabalin fails, the next line of defense are typically antidepressants such as SSRIs, which researchers believe may partly dampen pain processing by altering serotonin signalling in the nervous system. The last resort, Cioffi says, are opioids—highly addictive medications that blunt pain signals by mimicking natural endorphins. But even they don’t reliably work against neuropathy.
Tanmay Pati, a medicinal chemist at RPI and another study coauthor, saw those limitations firsthand after his father developed neuropathy following intensive radiation and chemotherapy for lymphatic cancer. “Fentanyl didn’t work much to reduce the pain,” Pati says, and the side effects ultimately outweighed the benefits.
When the drug became too “sticky”
As such, researchers have been highly motivated to find new ways of tackling neuropathy pain. Previous research in the 1990s identified a promising new target: a molecular recycling system called GlyT2 that helps regulate pain signalling in neurons in the spinal cord.
“The benefit of targeting GlyT2 is that it’s concentrated in the spinal cord rather than spread broadly throughout the brain,” says Ryan Patrick Cantwell Chater, the first author of the study and postdoctoral researcher at the University of Copenhagen who studies transporters in the central nervous system. “That allows us to potentially avoid some of the side effects you see with other targets.”
From 2001 to 2020, pharmaceutical company Organon developed a drug called ORG25543 that targets GlyT2. But despite years of work, the compound was abandoned before it ever reached clinical trials in humans. Experiments in animals identified serious side effects—including tremors, seizures, and death—at the doses needed for pain relief.
“We’re not talking about headaches and sedation here,” says Rob Vandenberg, a professor of pharmacology at the University of Sydney and another coauthor of the new study. “It’s not something that can just be dialed down.”
The authors of the new study now suspect that the very thing that made the compound effective — its extreme “stickiness” — was also what made it dangerous.
“When ORG25543 binds to GlyT2 it barely lets go. In pharmacology, we call that a long residence time,” Cioffi says. “We wanted to engineer a molecule that could still bind to GlyT2, but come off more rapidly — or be more reversible.”
From hundreds of candidates, a safer molecule emerges
The researchers then spent years redesigning the failed compound, evaluating nearly 300 related structures that they hoped would bind less aggressively to GlyT2. Eventually, one candidate emerged: RPI-GLYT2-82.
The new compound “has more rigidity in its structure than the Organon compound does, making it less likely to latch onto the transporter and stay there,” Cioffi says. The researchers also added chemical groups to make the molecule less “sticky.”
“For example, we added oxygen atoms to make the molecule less chemically ‘sticky.’”
The researchers then tested RPI-GLYT2-82 in mice with two forms of allodynia — a condition where normally harmless sensations such as cold or light touch become painful. They found the new drug worked about as well as pregabalin against cold-triggered neuropathic pain, although it was somewhat less potent against touch sensitivity.
Crucially, the researchers didn’t observe muscle weakness or drowsiness at the doses needed for peak pain relief — the very kinds of side effects that often limit existing neuropathy drugs.
“And the experiments showed that when you compare RPI-GLYT2-82 to morphine, there’s no addiction liability,” Shahsavar says.
Mapping the gate to better pain drugs
Through many hours of painstaking work at the electron microscope, the team also mapped out the structure of GlyT2 — the first human glycine transporter to be fully charted. It’s a shape-shifting molecular channel that adopts different configurations depending on its cellular surroundings.
“Now, we can visualize what areas of the protein we can probe and bind into,” says Chater, whose coauthors credit him with the lion’s share of the structure mapping.
“Since we got this structural data, we’ve been able to make modifications to the compound that look even more exciting,” Cioffi says. “Now we can actually see how the molecule fits into the transporter and interacts with it.”
“We really know what we’re doing now, rather than just guessing,” Vandenberg adds.
The team says they’ve already made additional tweaks to the drug candidate that they hope will improve its effectiveness. Early tests of the new candidate in mice, which haven’t yet been peer reviewed and published in a scientific journal, suggest it can match pregabalin in both mechanical and cold allodynia, Vandenberg says.
But it will be a while yet before neuropathy patients can ask for a prescription for RPI-GLYT2-82. The journey to the first clinical trials in humans could take about five years, Cioffi estimates.
When it comes time to put it through its paces in humans, the drug won’t need to eliminate neuropathic pain entirely to be considered a success, the researchers emphasize. Neuropathic pain is not a single disease but a broad category of disorders driven by many different biological mechanisms, meaning there will probably never be a single treatment that works for everyone.
A drug that works for even 10% of patients could still transform the lives of hundreds of thousands of people living with chronic nerve pain.
