International Research Team Develops Safer Opioid Candidate

UNC Researchers Help Develop Safer, Less Addictive Painkiller
October 20, 2016

Opioid addiction and overdose have rightly been in the public spotlight in recent years. Drug overdose is the leading cause of accidental death in the United States according to the American Society of Addiction Medicine and in 2014, heroin and prescription opioid drug overdoses combined to kill almost 30,000 Americans.

Even in North Carolina, where state programs have prevented thousands of deaths with anti-overdose drugs over the last two years, more than 1,300 North Carolinians died of drug overdose in 2014.

Now an international team of scientists, including pharmacologists from the UNC School of Medicine, have developed a new opioid drug candidate that could provide the pain-relief of other opioid drugs without the addictive qualities and other potentially deadly side effects. The paper describing this new drug was published in the journal Nature.

PillsFour out of every five new heroin users report that they started using heroin after an addiction to prescription drugs, and while the new drug candidate has only been used in mice so far, it could, with more research, revolutionize pain management in a country that wrote 259 million prescriptions for opioids in 2012.

Opioids, a class of drugs that includes all the synthetic and natural derivatives of opium, have been used medicinally for more than 2,000 years. These drugs made it possible to do extensive surgery and treat chronic pain. During the 1990s and 2000s, pain management and pain recognition became a higher priority in medicine and opioid prescriptions became more common.

The problem is that opioids have two unfortunate side effects. First, they alter the chemistry of the brain’s reward pathways, creating a need to seek out more of the drug. Second, and more dangerously, opioids fall into a class of substances called respiratory depressants, meaning they can slow down breathing even to the point of stopping it entirely. Respiratory depression and arrest are deadly symptoms resulting from opioid overdose and the reason why there is a limit to how much morphine patients can be given.

Researchers from Stanford University and the University of California, San Francisco began investigating how altering the chemistry of opioid drugs might be able to remove some of those side effects. To do that, Brian Shoichet, a pharmaceutical chemist at UCSF used tools unavailable to earlier generations of drug makers.

Since opium was first distilled from the poppy flower more than 5,000 years ago, opioid development has come by mixing it with other substances and altering its molecular structure to make the drugs we have today: trying a carbon here or an alcohol group there until a relatively safe and effective drug is made.

Thanks to Dr. Brian Kobilka, a molecular physiologist at Stanford, Nobel laureate and co-senior author of this study, the researchers were able to use a more targeted approach. Kobilka recently created the first molecular picture of the mu-opioid receptor—the part of the brain that latches onto opioid drugs to create their pain relieving effects.

mu-opioid receptorInstead of trying different chemicals one at a time on the actual receptor, UCSF researchers used a computer program to map how potential compounds could react with the opioid receptor. The computer ran through millions of molecules entering the receptor at millions of different bends and angles, cutting what could have been decades of research at a lab bench and in clinical trials to a period of just two weeks.

From millions of potential drugs, the computers at UCSF identified 23 that really showed promise. These particular compounds were designed to not only activate the mu-opioid receptor, but also avoid activating beta-arrestin-2, a biological pathway that causes both constipation and respiratory depression. UNC pharmacologists Dipendra Aryal and Dr. Bryan Roth then tested those 23 compounds in mice to determine which one worked best, and landed on a compound called PZM21, and along with German pharmacologists tweaked its chemistry to make the best drug they could.

This process puts PZM21 in a class completely by itself. By selecting from such a broad array of molecules, the researchers were able to find one chemically unrelated to morphine and other opiates, and as such it acts differently. Mice studies showed that the drug appeared to only work in the brain instead of both the brain and spinal cord like most opioids, and also does not stimulate beta-arrestin-2.

While the effects of beta-arrestin are well known, the researchers are not sure what effect activating the opioid receptors in the brain and not the spinal cord will have. That said, the mice showed some interesting behavior while they were on PZM21. 

The mice were always given PZM21 in the same part of their cages. The reason for that is that going back to the same spot looking for the drug becomes a conditioned response. Mice that become addicted will keep returning to the same spot looking for a fix, but curiously, the PZM21 didn’t spark this type of behavior in mice, suggesting they were not, in fact, addicted to it.

These results by no means prove that PZM21 is non-addictive, and many clinical trials will be needed to ensure this drug is safe and effective in humans. Still, the promise and possibility of a powerful pain reliever with less risk of addiction and deadly side effects could save thousands of American lives each year.

—Daniel Lane

Daniel Lane covers science, medicine, engineering and the environment in North Carolina.

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