Researchers are identifying potential drugs that make naloxone more potent and last longer

The ongoing opioid epidemic in the US kills tens of thousands of people each year. Naloxone, sold under the brand name Narcan, has saved countless lives by reversing opioid overdoses. But new and more powerful opioids continue to appear, and first responders are finding it increasingly difficult to revive people who overdose.

Now, researchers have found an approach that could extend the life-saving power of naloxone, 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 have identified potential drugs that make naloxone more potent and longer-lasting, able to reverse the effects of opioids in mice at low doses without worsen the withdrawal symptoms. The study is published July 3 in Nature.

Naloxone is a lifesaver, but it is not a miracle drug. has limitations. Many people who overdose on opioids need more than one dose of naloxone before they are out of danger. This study is a proof of concept that we can make naloxone work better -? last longer and are more powerful -? giving it in combination with a molecule that affects opioid receptor responses.”

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

Opioids such as oxycodone and fentanyl work by slipping into a pocket on the opioid receptor, which is found mainly on neurons in the brain. The presence of opioids activates the receptor, triggering a cascade of molecular events that temporarily change the way the brain works: reducing the perception of pain, inducing a sense of euphoria, and slowing breathing. This suppression of breathing is what 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 hot area of ​​research in pharmacology because they offer a way to influence how the body responds to drugs by modulating the activity of drug receptors rather than the drugs themselves. Co-author Vipin Rangari, PhD, a postdoctoral fellow in the Majumdar lab, performed the 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 the problematic opioids from the capsule, thus disabling the opioid receptor. The problem is that naloxone wears off before other opioids. For example, naloxone works for about two hours, while fentanyl can stay in the bloodstream for eight hours. Once the naloxone falls out of the binding pocket, any fentanyl molecules still circulating can reattach to the receptor and reactivate the receptor, causing the overdose symptoms to reoccur.

The research team -? led by co-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 -? we set out to find NAMs that enhance naloxone by helping it stay in the binding pocket longer and suppress opioid receptor activation more effectively.

To do so, they screened a library of 4.5 billion molecules in the lab for molecules that bind to the opioid receptor with naloxone already placed in the receptor pocket. Compounds representing several molecular families passed initial screening, with one of the most promising called compound 368. Further experiments in cells revealed that, in the presence of compound 368, naloxone was 7.6 times more effective at inhibiting receptor activation of opioids, in part because the naloxone stayed in the pocket of the binder 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 researcher in Kobilka’s lab at Stanford. “We think the naloxone has to bind first, and then compound 368 can come in and cover it in place.”

Even better, compound 368 improved naloxone’s ability to reverse opioid overdoses in mice and allowed naloxone to reverse the effects of fentanyl and morphine at 1/10 the usual doses.

However, people who overdose on opioids and are revived with naloxone may experience withdrawal symptoms such as pain, chills, vomiting, and irritability. In this study, while the addition of compound 368 enhanced the potency of naloxone, it did not exacerbate the withdrawal symptoms of the mice.

“We have a long way to go, but these results are really exciting,” McLaughlin said. “Opioid withdrawal probably won’t kill you, but it’s so severe that users often continue to take opioids within a day or two to stop the symptoms. The idea that we can save patients from overdose with reduced withdrawal might just to help a lot People.”

Compound 368 is only one of several molecules showing potential as an opioid receptor NAM. The researchers have filed a patent for NAMs and are working to narrow down and characterize the most promising candidates. Majumdar estimates it will be 10 to 15 years before a naloxone-boosting NAM is on the market.

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