An international team of scientists has developed a new opioid drug candidate that appears to block pain without triggering many of the risks associated with prescription painkillers.
The drug, called PZM21, was custom-engineered to dock with the brain’s morphine receptor and alleviate pain, but without inducing morphine’s sometimes deadly side effects, such as suppressing breathing.
“Morphine transformed medicine. There are so many medical procedures we can do now because we know we can control the pain afterwards,” says pharmacist Brian Shoichet from the University of California, San Francisco. “But it’s obviously dangerous too. People have been searching for a safer replacement for standard opioids for decades.”
PZM21 has so far only been tested on mice, but it could be the most promising morphine replacement scientists have found to date.
Shoichet and his team discovered the drug candidate after rigorous computer modelling, which saw the researchers perform approximately 4 trillion “virtual experiments” in the lab – designed to see what kinds of molecules would best fit with the atomic structure of the brain’s mu-opioid (morphine) receptor.
This approach signifies a new way of conducting drug discovery, focusing on what might best connect to our biological receptors themselves, rather than modifying the structure of a known chemical, like morphine, to see what effects small variations might have.
“We didn’t want to just optimise chemistry that already existed. We wanted to get new chemistry that would confer completely new biology,” says Shoichet. “When you start with the structure of the receptor you want to target… You’re empowered to imagine all sorts of things that you couldn’t even think about before.”
After the computer simulations, the team had found 23 candidate molecules deemed most likely to block pain without dangerously impairing breathing or causing constipation – another common side effect of opioids.
The researchers went through the shortlist to find the most potent chemical, then optimised it further, enhancing the molecular binding potency 1,000-fold. The resulting chemical was PZM21.
When tested on lab mice, the drug appeared to offer similar levels of pain relief to morphine, while showing reduced breathing impairment and constipation effects. The researchers also suggest that the drug might not be so addictive, because it doesn’t activate the brain’s dopamine systems.
In addition to this, the lab mice did not spend more time in test chambers where they had previously received PZM21 doses, which the scientists say could be evidence that the drug is not habit-forming – as similar testing with morphine is known to alter mouse behaviour in such a way. But they acknowledge that more work needs to be done to verify this hypothesis.
“We haven’t shown this is truly non-addictive,” says Shoichet. “At this point we’ve just shown that mice don’t appear motivated to seek out the drug.”
But the biggest question about PZM21 is whether the drug’s promising effects will safely translate to people, as many studies on animals fail to replicate their results in human trials.
A number of the researchers are now forming a new company to refine and test the chemical further, in the hopes that it could one day be commercialised – but that process will take time, and it could be years before we have more answers on how effective PZM21 ultimately is.
“I think this was really a tour de force,” Gavril Pasternak, an opioids researcher from the Memorial Sloan Kettering Cancer Centre in New York, who wasn’t involved in the study, told Angus Chen at NPR. “They’re new entities with totally different pharmacological profiles. These are great promise for opiates over the course of the next five to 10 years.”
The findings are published in Nature.