The extremely potent pain-relieving properties of morphine-derived opioids comes from their ability to activate a receptor on neurons called the mu opioid peptide (MOP). Yet as the opioid crisis has made bleakly, abundantly clear, drugs with this mechanism of action quickly induce tolerance, physical dependence, and a highly addictive release of neurotransmitters in the brain’s reward system. Not to mention the harmful immediate side effects of nausea, vomiting, and possibly fatal respiratory rate depression.
So naturally, developing new medications that maintain the analgesic properties of MOP agonists but lack their other baggage has been a high priority among drug researchers for many years. But thus far, all the candidates have fallen short.
Now, a team of pharmacologists have reported a potential breakthrough. In a series of experiments, their investigational compound AT-121 provided strong pain relief in monkeys without causing any adverse reactions, and animals given repeated doses showed no sign of dependency.
In their resulting paper, published in the journal Science Translational Medicine, the authors explain that AT-121 belongs to a class of a next-generation opioids known as bifunctional NOP/MOP agonists: In addition to activating MOP, the compound can also activate another, recently discovered opioid receptor known as nociceptin/orphanin FQ peptide (NOP). Past research in animals has shown that NOP agonists can boost the pain-signal blocking of MOP agonists while suppressing their unhelpful actions. And although several other bifunctional NOP/MOP drugs have been created in recent years, none have succeeded past the non-human primate testing phase.
After carefully designing AT-121 to have the ideal ratio of affinity between MOPs and NOPs, the team led by Huiping Ding at the Wake Forest School of Medicine evaluated the compound in 15 male and female rhesus monkeys. First, the researchers found that AT-121’s analgesic properties are about 100 times stronger than morphine and that even in high doses, the drug did not induce impaired movement, lowered breathing, or any other abnormal physiological changes.
Next, in an experiment where the monkeys could push a button to receive a dose of a variety of drugs, including cocaine and oxycodone, the animals chose to administer AT-121 with the same frequency that they chose a saline solution. When AT-121 was combined with oxycodone, the monkeys opted for the combo significantly less than they did when oxycodone alone was offered. These results indicate that AT-121 has a low potential for abuse on its own and that it could also be used to treat opioid dependence, similar to how buprenorphine is given to people addicted to heroin.
Finally, Ding’s group observed that monkeys given high doses of AT-121 for three days showed no symptoms of withdrawal.
“The fact that this data was in nonhuman primates, a closely related species to humans, was also significant because it showed that compounds, such as AT-121, have the translational potential to be a viable opioid alternative or replacement for prescription opioids,” author Mei-Chuan Ko said in a statement.
Moving forward, the group hope to gather more data from larger groups of primates. If all goes well, they will apply for FDA approval to begin a clinical trial in humans.