SCIENTISTS HAVE UNVEILED a new synthetic drug that appears to neutralise pain as effectively as morphine but without the side-effects that make opioids so dangerous and addictive.
In experiments with mice, the new compound, called PZM21, activated a known molecular pathway in the brain that triggers pain suppression. But unlike morphine and prescription drugs such as oxycodone or oxycontin, it did not switch on a second pathway that can slow or block normal breathing.
Respiratory suppression caused by opioids resulted in 249 deaths in Ireland in 2013. It was the same side-effect that lead to the death of Prince in April.
Nor did the new drug produce addiction in the lab mice, which get hooked on morphine and pharmaceutical painkillers as easily as humans. In experiments, the rodents showed no preference between a cubicle in which they had been administered PZM21 or one in which they received a neutral saline solution.
The big-data methods used by the researchers also open up a promising avenue in drug innovation.
The search for a safer painkiller
Opium and its derivatives have been used to dull pain (and generate euphoric feelings) for more than 4,000 years.
Even in the era of modern medicine, morphine, derived from the opium poppy, has remained the painkiller of choice, whether for post-op recovery or on the battlefield.
“But it is obviously dangerous too,” said Brian Shoichet, a professor at the University of California’s School of Pharmacy in San Francisco, and one of three senior authors of the study.
People have been searching for a safer replacement for standard opioids for decades.
A different method
Most such efforts have tried to tweak the drug’s chemical structure to get rid of the side-effects.
Shoichet and colleagues from Stanford University, the University of North Carolina and Friedrich-Alexander University in Bavaria, Germany, took a radically different approach.
Instead of trying to tweak morphine, they focused instead targeting the receptor in the brain which suppresses pain when activated.
Only the molecule that successfully “docks” with the receptor – like a key turning a lock – would work. But to avoid addiction and respiratory failure, that same molecule must not dock with a second receptor that provokes those unwanted reactions, which morphine does.
Using computer simulations, the researchers tested three million commercially available compounds and a million possible configurations for each one to see which would fit best with the receptor. In the lab, combing through trillions of options would have been prohibitively expensive and time-consuming.
Some 2,500 molecules met the conditions. After eliminating those resembling opioids too closely, 23 remained.
Only one of these activated the “good” molecular pathway without triggering the “bad” one. Even then, more custom-engineering was required.
Future
PZM21 still has many hurdles to overcome before showing up in pharmacies.
It must be proven safe for humans, and effective in clinical trials, a process that typically takes up to 10 years.
Future research will also need to determine whether mice or people develop a tolerance to the drug, causing it to lose its painkilling potency over time.
With additional reporting from Elizabeth O’Malley.
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