New Compound May Offer Power of Morphine With Less Risk
Preliminary studies in mice suggest an experimental drug called PZM21 is associated with less respiratory distress, constipation, and addictive properties than morphine while showing comparable analgesic potency.
Sifting through a haystack of over 3 million chemical compounds, a multidisciplinary team of investigators may have found a truly golden needle—a painkilling drug that offers the strength of morphine, but not the addictive properties or other serious health effects.
In preliminary mouse studies, this newly minted agent, known as PZM21, was found to be comparable in analgesic power to both morphine and TRV130, an experimental drug in phase 3 clinical studies; however, PZM21 provided relief for a longer time (up to three hours per dose, compared with two hours for morphine and one and a half hours for TRV130).
Unlike existing painkillers, this compound was associated with moderate constipation and did not cause any significant respiratory distress, which is the main cause of death due to an opioid overdose.
If these results hold up, then the risk of overdoses from PZM21 may be low, as mice given PZM21 also showed no preference for rooms containing this drug when given options to choose, tests known as conditioned place preference.
While the discovery of PZM21 provides some encouragement in the struggle against opioid addiction, another study published August 23 in Addiction highlights the severity of this public health problem. A 10-year assessment of nearly 3,400 military veterans—none of whom had taken an opioid drug at the study’s start—found that prescription opioid misuse led to a 5-fold increased risk of heroin use. Of the 500 participants who initiated heroin use between 2002 and 2012, 77 percent reported prior or concurrent nonmedical prescription painkiller use.
Other risk factors for heroin use identified in the analysis included being male (2.6-fold risk), African American (2-fold risk), or abusing stimulant drugs (2.1-fold risk). Receiving a prescription for an opioid painkiller was not a significant risk factor for heroin use, though; short-term prescriptions incurred a 1.7-fold risk, while longer-term prescriptions had no statistically significant risk. This suggests most opioids were acquired nonmedically, and the study authors recommended that health care professionals who serve veterans should watch closely for signs of nonmedical use of opioid painkillers.
An abstract of “Nonmedical Use of Prescription Opioids Is Associated With Heroin Initiation Among U.S. Veterans: A Prospective Cohort Study” can be accessed here.
Brian Shoichet, Ph.D., a professor of pharmaceutical sciences at the University of California, San Francisco, and one of the lead investigators in this work, did caution that these preference studies haven’t yet ruled out an addictive potential for PZM21.
“We’ve only shown so far that this drug doesn’t activate any reinforcing behaviors, but further animal studies are needed that more directly test addiction,” he told Psychiatric News. Additional testing is also needed to ensure that long-term use does not lead to any toxicity.
“So PZM21 still has a long way to go before any clinical application, and there could be a potential dead end any step along the way,” he continued. “But we are cautiously optimistic at this point, and there haven’t been any hints of a showstopper yet.”
The discovery of PZM21 was first made possible in 2012 when researchers at Stanford University led by Nobel laureate Brian Kobilka, Ph.D., identified the three-dimensional architecture of the mu opioid receptor, the target of morphine and related drugs.
Kobilka then passed the baton to Shoichet, a frequent collaborator with an expertise in molecular docking—the discipline of finding just the right molecule to fit the pocket of a target receptor.
Shoichet and his lab first ran their collection of 3 million potential drugs through a computer-based screening program that modeled over 1 million possible docking configurations for each compound (a scale that would not have been possible 10 or 15 years ago). They then chose the top 2,500 molecules that had some docking potential and winnowed this list down to 23 promising candidates, which were tested in laboratory assays.
Seven of these bound to the receptor strongly enough to be considered viable, and some chemical tweaking of the structures and further lab tests carried out by colleagues at the University of North Carolina and Florida Atlantic University eventually produced the final product and potential boon for the growing opioid epidemic.
“I think it’s important to point out that we managed to translate a basic molecular discovery into an experimental drug in just a few years,” Soichet said. “These exciting results arose from fundamental research.”
The results of this collaborative effort were published August 17 in Nature. The study was supported by grants from the National Institutes of Health and German Research Foundation, as well as the Michael Hooker Distinguished Professorship. ■
An abstract of “Structure-Based Discovery of Opioid Analgesics With Reduced Side Effects” can be accessed here.
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Published online: 6 October 2016
Published in print: September 17, 2016 – October 7, 2016
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