New Painkiller Is Like Morphine With Few Side Effects

New Painkiller Is Like Morphine With Few Side Effects

New Painkiller Is Like Morphine With Few Side Effects by Mark Derewicz-UNC, Futurity

Scientists are designing a new opioid drug that blocks pain as effectively as morphine without dangerous side effects.

In particular, the new drug does 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 and sometimes severe opioid side effect.

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In lab tests, the new drug also appears to side-step the brain’s dopamine-driven addiction circuitry and does 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, researchers say. But if the findings are borne out, the drug could transform the fight against the ongoing epidemic of prescription painkiller addiction.

Modern medicine depends on these drugs as our most powerful weapon against pain.

“Morphine transformed medicine,” says Brian Shoichet, a professor of pharmaceutical chemistry in UC San Francisco’s School of Pharmacy and co-senior author on the new paper in Nature. “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.”

How they made it

Much of drug discovery, Shoichet says, begins by taking a successful drug like morphine and tweaking its structure to try to get rid of side effects while maintaining its primary function. The new study took a different, much more radical approach: “We didn’t want to just optimize chemistry that already existed,” Shoichet says. “We wanted to get new chemistry that would confer completely new biology.”

Key to the new paper was knowing the atomic structure of the mu-opioid receptor, the brain’s “morphine receptor,” which was recently deciphered by co-senior author and 2012 Nobel laureate Brian Kobilka, a professor of molecular and cellular physiology at the Stanford University School of Medicine.

With this structural information in hand, Shoichet’s team turned to a computational approach called molecular docking, which was pioneered in the 1980s at by Shoichet’s mentor, Tack Kuntz.

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

They also wanted 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 judged by the software and the research team to be most likely to activate the mu-opioid receptor in the way the researchers wanted.

Only then did the team actually test these candidate drugs in the real world.

Co-lead author Dipendra Aryal led a team of researchers in the pharmacology lab of co-senior author Bryan Roth, a professor of pharmacology at the University of North Carolina (UNC) School of Medicine, to identify the most potent of the 23 leading candidates.

Then, Roth’s team worked with the lab of co-senior author Peter Gmeiner, chair and professor of medicinal chemistry at the Friedrich-Alexander University Erlangen-Nürnberg in Germany, to optimize 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.

‘Unprecedented, weird, and cool’ new biology

In further pharmacological tests conducted in the Roth lab, PZM21 exhibited the “new biology” the researchers had been looking for: efficiently blocking pain without producing the constipation and breathing suppression typical of traditional opioids.

“After we replicated the lab experiments and mouse studies several times, then I became excited about the potential of this new drug candidate,” Roth says.

In addition, PZM21 appeared to dull pain by affecting opioid circuits in the brain only, with little effect the on opioid receptors in the spinal cord that mediate pain reflexes. No other opioid has such a specific effect, Shoichet says, calling it “unprecedented, weird, and cool.”

Additional behavioral tests in mice suggested the drug may also lack the addictive qualities of existing opioids. Specifically, the drug didn’t produce the hyperactivity other opioids trigger in mice by activating the brain’s dopamine systems—which are also involved in addiction.

Perhaps more tellingly, mice did not spend more time in test chambers where they had previously received doses of PZM21—a test called “conditioned place preference.” Spending more time in those chambers is considered a correlate of human drug-seeking behavior.

“We haven’t shown this is truly non-addictive,” Shoichet cautions, emphasizing that further animal experiments and human studies would be needed to establish the compound’s addictive potential. “At this point we’ve just shown that mice don’t appear motivated to seek out the drug.”

“This promising drug candidate was identified through an intensively cross-disciplinary, cross-continental combination of computer-based drug screening, medicinal chemistry, intuition, and extensive preclinical testing,” Kobilka says.

“If you took away any one of these collaborators it simply wouldn’t have worked,” Shoichet adds. “Without Kobilka’s structure, our computation, Roth’s pharmacology, and Gmeiner’s ability to put an atom in exactly the place you want it, this never would have been possible.”

The US National Institutes of Health and grants from other organizations funded the study.

Source: UNC-Chapel Hill

Original Study DOI: 10.1038/nature19112

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