Potent killer drug resists treatment from naloxone.Police officers, firefighters, and paramedics have been trained to save the lives of many overdose victims by administering naloxone, a drug that reverses the deadly effects of opioids such as heroin. But the recent flood of fentanyl into America—a synthetic opioid designed for severe and chronic pain relief that packs a punch 50 to 100 times greater than heroin—has stymied many life-saving efforts of first responders.
Naloxone is effective at rapidly reversing an opioid overdose when administered because it replaces the deadly opioids in the opioid receptors.
“Naloxone binding to an opioid receptor turns it mostly off, but not all the way,” said Evan O’Brien, the lead author of the new study, in a press release. “Our data shows that compound 368 is able to increase the binding of naloxone and turn the receptor off more completely.”
The researchers, who searched through billions of compounds to find this one, said it can bind next to naloxone in the receptors.
Working with mice, the scientists found that when they exposed cells with opioid receptors to compound 368, there was little effect. But when they combined 368 with naloxone, opioids were more effectively blocked from binding. The more of this newly discovered compound was added, the better naloxone blocked opioids, including fentanyl and morphine.
Compound 368 Ineffective by Itself
To discover the impact of the substances, mice were given morphine, one of the most widely used opioids.
Because opioids reduce the sensation of pain, researchers tested how quickly the mice removed their tails from hot water to see the effects of varying doses of opioid antidotes. When the mice on morphine were given compound 368 alone, there was no difference in the length of time it took the mice to remove their tails from the water. In other words, the sensation of pain was the same with or without compound 368.
This confirmed that the compound was only effective when administered with naloxone.
“The compound in mice, at least from the assays we’ve run, does nothing on its own,” Mr. O’Brien said. “We don’t see anything happen to the mice even when we inject a massive amount of compound 368.”
Then, mice were given small doses of naloxone, an amount that typically would have no effect, with compound 368.
New Compound Reverses Respiratory Depression
In addition to reducing pain, a small dose of naloxone with compound 368 reversed respiratory depression in mice, a frequent cause of death in human overdose victims, the researchers said in their press release.
They said a half dose of naloxone with compound 368 “was strong enough to counter fentanyl.”
Mr. O’Brien said no side effects were observed in mice injected with compound 368, even when the researchers gave them a “massive amount” of the compound.
“The more tools at our disposal, the better we’ll be able to fight this epidemic of fentanyl overdoses,” he said.
