A cross-country research team has identified a promising approach to improving the life-saving function of naloxone (Narcan), a drug used to reverse opioid overdose. The researchers published their study entitled, “A µ-opioid receptor modulator that works cooperatively with naloxone” in Nature.

Professors Susruta Majumdar, PhD, Washington University, Brian K. Kobilka, PhD, Stanford University, and Jay P. McLaughlin, PhD, University of Florida collaborated on the project to identify compounds that enhance naloxone’s potency and longevity following treatment. Their team identified a compound that fits these criteria while also reducing withdrawal symptoms in the mice test subjects, even at low doses.

“Naloxone is a lifesaver, but it’s not a miracle drug; it has limitations,” said Majumdar. “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 be more potent—by giving it in combination with a molecule that influences the responses of the opioid receptor.”

Opioids like oxycodone and fentanyl function by binding to the opioid receptors in the brain to reduce pain perception. Concurrently, with pain reduction, opioids can also induce euphoria, and reduce breathing rate. Overdosing usually occurs as a result of too slowed breathing.

Naloxone reverses opioid overdoses by blocking the ability of the opioid to bind to receptors in target cells. It is fast acting at reversing opioid effects, but it wears off more quickly than many stronger opioids take to be cleared from the blood stream, allowing the overdose symptoms to return. Even when overdose is reversed successfully, withdrawal symptoms can often be so severe that opioid use may restart.

In the current study, the team screened 4.5 billion molecules to identify compounds that can improve the function of naloxone. One of the most promising compounds is a negative allosteric modulator (NAM), simply dubbed compound 368.

“The compound itself doesn’t bind well without naloxone,” said lead author Evan O’Brien, PhD, postdoctoral researcher at Stanford University. “We think naloxone has to bind first, and then compound 368 is able to come in and cap it in place.”

While compound 368 is ineffective on its own, when combined with naloxone, the opioid receptor is blocked from binding to opioids for at least ten times longer than naloxone treatment alone. The combination also results in naloxone being 7.6 times more effective in inhibiting the opioid receptor activation. O’Brien pointed out that “compound 368 is able to increase the binding of naloxone and turn the receptor off more completely.”

Importantly, the team didn’t find any off-target effects from the compound. “We don’t see anything happen to the mice even when we inject a massive amount of compound 368,” O’Brien shared. This adds promising data to support future clinical trials in humans.

“We have a long way to go, but these results are really exciting,” McLaughlin said.

Majumdar concurred, adding, “Developing a new drug is a very long process, and in the meantime new synthetic opioids are just going to keep on coming and getting more and more potent, which means more and more deadly. Our hope is that by developing a NAM, we can preserve naloxone’s power to serve as an antidote, no matter what kind of opioids emerge in the future.”

The team will continue their work with compound 368 and other molecular candidates that may be NAMs of the opioid receptor. O’Brien points out that “allosteric modulators are not common yet, and they’re a lot more difficult to discover and to work with.”

The eventual goal is to bring a naloxone enhancing product to market. “We’re still working on optimizing the compound’s properties for those longer-lasting effects,” O’Brien said. “But first showing that it works cooperatively with these low doses of naloxone suggests that we’re on the right track.”

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