Adding a newly identified compound makes naloxone more potent, longer-lasting, mouse study shows

The ongoing opioid epidemic in the US kills tens of thousands of people each year. Naloxone, sold under the brand name Narcan, has saved many lives by reversing opioid overdoses. But new and stronger opioids are emerging, and first responders are finding it difficult to rehabilitate addicts.

Now, researchers have found a way to increase the life-saving power of naloxone, even in the face of opioids that are still dangerous. A group of researchers at the Washington University School of Medicine in St. Louis, Stanford University and the University of Florida have identified a drug that may make naloxone more potent and long-lasting, able to reverse the effects of opioids in mice at low doses without worsening removed. symptoms. The study was published on July 3 at Nature.

“Naloxone is a lifesaver, but it’s not a miracle drug; it has limitations,” said co-author Susruta Majumdar, Ph.D., a professor of anesthesiology at the University of Washington.

“Many people who overdose on opioids need more than one dose of naloxone before they get out of danger. This study is proof of concept that we can make naloxone more effective—it lasts longer and be potent—by giving it together with a molecule that stimulates opioid receptor responses.”

Opioids such as oxycodone and fentanyl work by binding to the opioid receptor, which is found primarily on neurons in the brain. The presence of opioids activates the fluid, triggering molecular events that temporarily change the way the brain works: reducing pain, creating euphoria and reducing breathing. It is this suppression of breathing that makes opioids so lethal.

The molecular compound described in the paper is a so-called negative allosteric modulator (NAM) of the opioid receptor. Allosteric modulators are a hot area of ​​pharmacology research, because they provide a way to influence the body’s response to drugs by modifying the activity of drug receptors rather than the drugs themselves. . Co-author Vipin Rangari, Ph.D., a postdoctoral fellow in Majumdar’s laboratory, conducted experiments to chemically characterize the compound.

Naloxone is an opioid, but unlike other opioids, its presence in the binding pocket does not activate the receptor. This unique property gives naloxone the ability to reverse overdose by removing problematic opioids from the pocket, thus disabling the opioid system.

The problem is that naloxone wears off before other opioids do. For example, naloxone works for about two hours, while fentanyl can stay in the blood for eight hours. Once the naloxone falls into the binding pocket, any circulating fentanyl molecules can bind again and reactivate the receptor, causing the overdose symptoms to return.

The research team, led by co-authors Majumdar; Brian K. Kobilka, Ph.D., professor of molecular and cellular physiology at Stanford University; and Jay P. McLaughlin, Ph.D., professor of pharmacodynamics at the University of Florida, aim to find NAMs that enhance naloxone by helping it stay in the binding pocket longer and blocking opioid receptor activation successfully.

To do so, they screened a library of 4.5 billion molecules in the lab to look for molecules that bind to the opioid receptor and naloxone that has been inserted into the receptor pocket. Chemicals representing several families of molecules went through the first screen, with one of the most promising chemicals named 368.

Further cell tests revealed that, in the presence of compound 368, naloxone was 7.6 times more effective at blocking opioid receptor activity, in part because naloxone remained in the bag. which is binding at least 10 times longer.

“The compound itself doesn’t bind well without naloxone,” said Evan O’Brien, Ph.D., the study’s lead author and a postdoctoral fellow in Kobilka’s lab at Stanford. “We think the naloxone has to bind first, and then compound 368 is able to go in and lock it in place.”

Even better, compound 368 improved naloxone’s ability to combat opioid overdose in mice and enabled naloxone to reverse the effects of fentanyl and morphine at 1/10th the usual dose.

However, people who overdose on opioids and are revived with naloxone can experience withdrawal symptoms such as pain, confusion, vomiting and irritability. In this study, while the addition of compound 368 enhanced the efficacy of naloxone, it did not worsen the withdrawal symptoms in mice.

“We have a long way to go, but these results are exciting,” McLaughlin said. “Opioid withdrawal may not kill you, but it’s so severe that users often start taking opioids within a day or two to stop the symptoms. people.”

Compound 368 is one of several molecules that show potential as opioid receptor NAMs. Researchers have filed a patent on NAMs, and are working to narrow down and identify the most promising candidates. Majumdar estimates that it will be 10 to 15 years before NAM’s improved naloxone is brought to market.

“Developing a new drug is a very long process, and in the meantime new synthetic opioids will continue to come and become more potent, which means more lethal,” said Majumdar. “Our hope is that by developing NAM, we can preserve naloxone’s ability to act as an antidote, no matter what kind of opioids appear in the future.”