New opioid candidate may help reduce overdoses

The main cause of opioid overdose is respiratory suppression, but researchers have identified a compound that mimics commonly used drugs’ painkilling effects and lacks that lethal characteristic.

In a collaborative study, scientists at multiple U.S. universities found the drug candidate PZM21, which was tested in mice, resembles morphine and other drugs like it, but may be less addictive. The compound could one day help reduce the nearly 30,000 drug overdose deaths from respiratory suppression that occur annually in the United States, they argued.

“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,” senior investigator Dr. Brian Kobilka, a molecular and cellular physiology professor at Stanford University, said in a news release.

To set about identifying a new drug candidate, researchers studied two related chemical reactions, or molecular pathways: one that’s involved with analgesia and one responsible for respiratory suppression. Researchers had to figure out a way to separate those reactions because the drug’s necessary painkilling benefit sets off the unwanted respiratory effect.

“The field had wondered whether a small molecule with just the right chemical features to trip off one pathway, but not the other, could be designed,” study author Dr. Aashish Manglik, Ph.D. a recent graduate of Stanford’s Medical Scientist Training Program, said in the release.

Researchers at Stanford; the University of California, San Francisco; the University of North Carolina at Chapel Hill; and Florida Atlantic University (FAU), used computational screening to study binding properties of 2,500 compounds, which they eventually narrowed down to 23 then a few a dozen.

Study author Dr. Bryan Roth, Ph.D., pharmacology professor and medicinal chemistry at UNC, analyzed the candidates further and identified one that strongly activated the “good” pathway without the “bad” one, according to the release. Researchers collaborated with study author Peter Gmeiner, Ph.D., chair of medicinal chemistry at FAU, to optimize the compound’s painkilling effect by creating numerous versions of it, adding a new chemical feature, and observing the final product’s binding effect performed better than it did in its original form.

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Further testing suggested the product, PZM21, didn’t affect other opioid receptors— namely kappa, which causes uneasiness and hallucinations, and is characteristic of morphine and oliceridine, a drug currently in phase 3 trials. If developed, PZM21 could offer a painkiller solution to individuals who struggle with those side effects.

Subsequent research of mice revealed the compound relieved pain as successfully as that of morphine but did not cause respiratory suppression. Mice also didn’t show a preference between chambers that housed injections of a solution containing PZM21 and another otherwise identical solution lacking PZM21, which suggested the compound wasn’t addictive. According to the release, it’s well known that mice are preferential to chambers with morphine.

Study authors validated the efficacy of the compound when they saw PZM21 had no effect on mice bioengineered to lack the opioid receptor in question. Next, researchers plan to further develop the drug and negotiate licensing.