Researchers Develop Safer Opioid Painkiller From Scratch


New Compound, Tested in Mice, Could Reduce Overdoses and Possibly Curb Addiction

Scientists, including one of Indian origin, have created a new drug that blocks pain without triggering potentially deadly side effects of current prescription painkillers.

Researchers, including Aashish Manglik from Stanford University, custom-engineered the drug from scratch, using computational techniques to explore more than four trillion different chemical interactions.

In a new study — published online Aug. 17, 2016, in Nature — the researchers used the newly deciphered atomic structure of the brain’s “morphine receptor” to custom-engineer a novel drug candidate that blocked pain as effectively as morphine in mouse experiments, but did not share the potentially deadly side effects typical of opioid drugs. In particular, the new drug did not interfere with breathing — the main cause of death in overdoses of prescription painkillers as well as street narcotics like heroin — or cause constipation, another common opioid side effect. The new drug also appears to side-step the brain’s dopamine-driven addiction circuitry and did not cause drug-seeking behavior in mice.

More work is needed to establish that the newly formulated compound is truly non-addictive and to confirm that it is as safe and effective in humans as it is in rodents, the authors say. But if the findings are borne out, they could transform the fight against the ongoing epidemic of prescription painkiller addiction.

Deaths from opioid drug overdoses have been on the rise in the US for decades. According to the Centers for Disease Control and Prevention, 28,000 Americans died of narcotic overdoses in 2014, four times more than in 1999, with more than half of these deaths involving prescription drugs. The epidemic has gotten the attention of national leaders: in February, 2016, President Obama proposed $1.1 billion in new funding for opioid addiction treatment, and in July Congress passed the Comprehensive Addiction and Recovery Act, a bill intended to curb opioid abuse and improve treatment.

But as damaging as opioids can be, modern medicine depends on these drugs as our most powerful weapon against pain.

“Morphine transformed medicine,” said Brian Shoichet, PhD, a professor of pharmaceutical chemistry in UCSF’s School of Pharmacy and co-senior author on the new paper. “There are so many medical procedures we can do now because we know we can control the pain afterwards. But it’s obviously dangerous too. People have been searching for a safer replacement for standard opioids for decades.”

The atomic structure of the mu-opioid receptor, the brain’s “morphine receptor,” which was recently deciphered by 2012 Nobel laureate Brian Kobilka, a professor at the Stanford University School of Medicine.

With this structural information in hand, researchers turned to a computational approach called molecular docking.PZM21

In a two-week period, they performed roughly four trillion “virtual experiments” on a computer cluster, simulating how millions of different candidate drugs could turn and twist in different angles to find those configurations that were most likely to fit into a pocket on the receptor and activate it.

They also strove to avoid molecules that could stimulate beta-arrestin2, part of a biological pathway linked to the respiratory suppression and constipation typical of other opioids.

This led to a short-list of 23 candidate molecules. These were tested in the real world to identify the most potent one among the candidate drugs.                         PZM21, the new, safer opioid drug candidate, is shown docked on                                                                       the brain’s morphine receptor, the mu-opioid receptor. Image by                                                                           Anat Levit

Researchers, including those from Friedrich-Alexander University Erlangen-Nurnberg in Germany, then optimised this compound’s chemical efficacy 1000-fold.

This approach succeeded in producing a molecule that the researchers called PZM21, which is chemically unrelated to existing opioid drugs.