Scientists have identified potential drugs that enhance naloxone’s effectiveness and prolong its effects.

The ongoing opioid epidemic in the United States kills tens of thousands of people each year. Naloxone, sold under the brand name Narcan, has saved countless lives by reversing opioid overdoses. But modern and more potent opioids continue to emerge, and first responders are finding it increasingly arduous to resuscitate people who have overdosed.

Now, scientists have discovered an approach that could extend naloxone’s life-saving power even in the face of increasingly threatening opioids. A team of researchers from Washington University School of Medicine in St. Louis, Stanford University and the University of Florida have identified potential drugs that make naloxone more potent and last longer, and that can reverse the effects of opioids in mice at low doses without worsening withdrawal symptoms. The study was published July 3 in the Nature.

Naloxone saves lives, but it’s not a miracle drug; it has its limitations. Many people who overdose on opioids need more than one dose of naloxone before they’re out of harm’s way. This study is proof of concept that we can make naloxone work better – longer and more potent – by giving it in combination with a molecule that affects opioid receptor responses.

Susruta Majumdar, PhD, co-author, professor of anesthesiology at the University of Washington

Opioids like oxycodone and fentanyl work by slipping into a pocket on the opioid receptor, which is found mostly on neurons in the brain. The presence of opioids activates the receptor, setting off a cascade of molecular events that temporarily changes the way the brain functions: reducing the perception of pain, inducing a sense of euphoria, and slowing breathing. It’s this suppression of breathing that makes opioids so deadly.

The molecular compound described in the paper is a so-called negative allosteric modulator (NAM) of the opioid receptor. Allosteric modulators are a scorching area of ​​research in pharmacology because they offer a way to influence how the body responds to drugs by fine-tuning the activity of drug receptors rather than the drugs themselves. Co-author Vipin Rangari, PhD, an assistant professor in Majumdar’s lab, 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 feature gives naloxone the power to reverse overdoses by displacing problematic opioids from the pocket, thereby deactivating the opioid receptor. 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 naloxone falls out of the binding pocket, any fentanyl molecules still circulating can reattach to the receptor and reactivate it, causing the overdose symptoms to return.

The research team, led by senior authors Majumdar, Brian K. Kobilka, PhD, professor of molecular and cellular physiology at Stanford University, and Jay P. McLaughlin, PhD, professor of pharmacodynamics at the University of Florida, set out to find NAMs that enhance naloxone, helping it stay in the binding pocket longer and more effectively inhibit opioid receptor activation.

To do this, they searched the lab’s library of 4.5 billion molecules for molecules that bind to the opioid receptor, where naloxone is already tucked away in the receptor pocket. Compounds representing several molecular families passed initial testing, and one of the most promising was named compound 368. Further experiments in cells showed that in the presence of compound 368, naloxone was 7.6 times more effective at inhibiting opioid receptor activation, in part because naloxone stayed in the binding pocket at least 10 times longer.

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

Furthermore, compound 368 improved the ability of naloxone to counteract opioid overdose in mice and allowed naloxone to reverse the effects of fentanyl and morphine at 1/10th of the usual doses.

However, people who have overdosed on opioids and are revived with naloxone can experience withdrawal symptoms, such as pain, chills, vomiting, and irritability. In this study, although adding compound 368 increased the potency of naloxone, it did not worsen withdrawal symptoms in mice.

“We still have a long way to go, but these results are really exhilarating,” McLaughlin said. “Opioid withdrawal probably won’t kill you, but it’s so severe that users often go back to taking opioids within a day or two to stop the symptoms. The idea that we can save patients from overdosing by reducing withdrawal symptoms could support a lot of people.”

Compound 368 is just one of several molecules that show potential as an opioid receptor NAM. The researchers have filed a patent for the NAM and are working to narrow down and characterize the most promising candidates. Majumdar estimates it will be 10 to 15 years before a naloxone-enhancing NAM is commercially available.

“Developing a modern drug is a very long process, and in the meantime, modern synthetic opioids will come along and become more potent, which means they will become more lethal,” Majumdar said. “Our hope is that by developing NAM, we can preserve the potency of naloxone to serve as an antidote, no matter what opioids come along in the future.”