The ongoing opioid crisis in the United States claims thousands of lives each year. Naloxone (its brand name is Narcan) has saved countless lives by reversing opioid overdoses. However, as new, more potent opioids become available, first responders face increasing challenges in resuscitating overdose victims.

Now, researchers have found a way to extend naloxone's life-saving power even in the face of increasingly dangerous opioids. A team of researchers from Washington University School of Medicine in St. Louis, Stanford University, and the University of Florida has discovered a potential drug that makes naloxone more potent and lasts longer, reversing the effects of opioids at low doses in mice without worsening withdrawal symptoms. The research was published in the July 3 issue ofnature"magazine.

"Naloxone is a life-saving drug, but it's not a miracle drug; it has limitations," said co-first author Susruta Majumdar, Ph.D., professor of anesthesiology at the University of Washington. "Many people who overdose on opioids need more than one dose of naloxone to get out of harm's way. This study is proof of concept that we can make naloxone work better -- last longer and be more potent -- by combining it with a molecule that affects the response of opioid receptors."

Opioids like oxycodone and fentanyl work by slipping into pockets of opioid receptors, which are primarily found on neurons in the brain. The presence of opioids activates receptors, triggering a cascade of molecular events that temporarily alters the brain's function: reducing pain sensations, producing a feeling of euphoria, and slowing breathing. It's this respiratory depression that makes opioids so deadly.

The molecular compound described in the paper is a so-called negative ectopic modulator (NAM) of opioid receptors. Xenotopic modulators are a popular area of ​​pharmacological research because they provide a way to influence the body's response to drugs by fine-tuning the activity of drug receptors rather than the drug itself. Study co-author Vipin Rangari, Ph.D., a postdoctoral researcher in Majumdar's lab, chemically characterized the compound experimentally.

Naloxone is an opioid, but unlike other opioids, its presence in the binding pocket does not activate the receptors. This unique feature of naloxone displaces problematic opioids from their binding pockets, thereby inactivating opioid receptors and thus reversing an overdose. The problem is that naloxone wears off earlier than other opioids. For example, naloxone lasts about two hours, while fentanyl can stay in the blood for eight hours. Once naloxone escapes from the binding pocket, any fentanyl molecules still circulating can reattach and reactivate the receptors, causing overdose symptoms to return.

A research team led by co-first author 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, began looking for NAMs that could help naloxone stay in the binding pocket longer and inhibit the activation of opioid receptors more effectively, thereby enhancing the effects of naloxone.

To do this, they screened a library of 4.5 billion molecules in the lab, looking for molecules that would bind to the opioid receptors where naloxone had been stuffed into the receptor pockets. Compounds representing multiple molecular families passed the preliminary screening, and the most promising compound was named 368. Further experiments in cells showed that naloxone was 7.6 times more effective at inhibiting opioid receptor activation in the presence of compound 368, in part because naloxone remained in the binding pocket at least 10 times longer.

"Without naloxone, the compound itself doesn't bind well," said Dr. Evan O'Brien, lead author of the study and a postdoc in Kobilka's lab at Stanford. We think the naloxone has to bind first and then compound 368 can come in and immobilize it."

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 1/10 the usual dose.

However, people who overdose on opioids can experience withdrawal symptoms such as pain, chills, vomiting, and irritability after using naloxone. In this study, while adding Compound 368 increased the potency of naloxone, it did not worsen withdrawal symptoms in the mice.

"We still have a long way to go, but these results are really exciting," McLaughlin said. "Opioid withdrawal may not be fatal, but the withdrawal symptoms are severe and users often resume taking opioids within a day or two to relieve symptoms. The idea that we can save overdose patients by reducing withdrawal could help a lot of people."

Compound 368 is just one of several molecules that has shown potential as an opioid receptor NAM. The researchers have patented these NAMs and are working to narrow down and characterize the most promising candidate molecules. Majumdar estimates that naloxone-enhanced NAM will be on the market in 10 to 15 years.

"Developing a new drug is a very long process, and during that time, new synthetic opioids are constantly emerging and becoming more and more potent, which means more and more deadly," Majumdar said. "Our hope is that by developing naloxone, we can maintain the power of naloxone as an antidote no matter what opioids appear in the future."

Compiled from /ScitechDaily

DOI:10.1038/s41586-024-07587-7