“We're cautiously optimistic,” said Aashish Manglik, an instructor in molecular and cellular physiology at Stanford University's School of Medicine and one of the study's co-lead authors. He noted that the finding “hints at the possibility that there may be a possible way to separate analgesia from some of these side effects.”

The study also involved researchers from the University of California-San Francisco, the University of North Carolina, and Friedrich-Alexander University Erlangen-Nürnberg.

New molecule kills pain

The new molecule targets the brain-mediated emotional component of pain. This allows it to kill pain just as well as morphine does, without the side effects of respiratory suppression and dopamine-driven addiction in the brain. (Regular painkillers target both the brain-mediated and reflexive response aspects of pain, while this drug addresses only the brain-mediated response.) The new drug also causes less constipation and doesn't affect spinal cord reflexive responses as traditional narcotics do, according to the study.

The difference in addiction was shown in experiments involving mice. The specimens showed no preference for test chambers that included a solution containing PZM21, compared with chambers that didn't. In the same test, when one of the chambers had morphine, mice spent more time there. Both results distinguished the new compound from other painkillers and from Oliceridine, a comparable molecule developed by Trevena, Inc. that's in clinical trials, Manglik said.

“What we've done is find new chemical matter, molecules that are really quite different from previously characterized opiates,” he said.

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The new compound was identified using 2012 findings by Manglik and others in the lab of Brian Kobilka, a Stanford professor of molecular and cellular physiology and a Nobel Laureate. (Kobilka was a co-senior author of the new paper.) In the earlier research, scientists described the atomic structure of the mu opioid receptor, through which painkillers such as morphine act. Understanding how the receptor interacts with morphine or other drugs let the PZM21 developers replicate morphine's benefits without setting off chemical reactions that suppress breathing.

With that information in hand, researchers were able to screen about 3 million compounds, using 4 trillion virtual simulations, to see which ones produced the right interaction with the mu opioid receptor. They came up with a short list of 23 candidates and found one that caused the right reactions after interacting with the mu opioid receptor. Then they strengthened it by a factor of 1,000.

Years of human testing ahead

Manglik estimates that it will take multiple years for the compound to be tested in humans, noting the importance of such trials to learn more about PZM21's addictive properties and safety. “The real experiment for a lot of these things is going to have to happen in humans,” he said, adding that addiction is “really a human disease.”

While more testing is done to replace addictive opioids, the work on PZM21 may bear fruit in many other areas of medicine. The researchers studied a large family of receptors that communicate messages to cells, not just the mu opioid receptor, so a similar approach could yield new types of drugs for other conditions.

“It's a good example of how the type of work that we do has the potential for impact in pretty large areas of medicine,” Manglik said.

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