A Bifunctional Opioid Is Analgesic—and Safe—in Nonhuman Primates
The search for a safer opioid has revealed a new candidate. A team led by Mei-Chuan Ko, Wake Forest School of Medicine, Winston-Salem, US, and Nurulain Zaveri, Astraea Therapeutics, Mountain View, US, has now identified a dual nociceptin/mu opioid receptor (MOR) agonist that’s analgesic but lacks the usual set of opioid side effects, at least in nonhuman primates.
Dubbed AT-121, the bifunctional opioid produced antinociceptive and anti-allodynic responses in a small number of rhesus macaque monkeys. But unlike currently available opioids, the compound did not cause respiratory depression, tolerance, hyperalgesia, withdrawal, or reinforcement. What’s more, it rendered oxycodone less reinforcing, hinting at the possibility that it could help treat opioid addiction.
“A dual nociceptin/mu opioid receptor agonist is not a completely novel idea, but so far, AT-121 has the cleanest profile I’ve seen. It certainly seems to be very promising,” said John Streicher, a pharmacologist at the University of Arizona, Tucson, US, who was not involved in the study.
The work was published August 29, 2018, in Science Translational Medicine.
A dual agonist
Recently, efforts to find a safer opioid have yielded encouraging results. In September 2016, a team of labs at the University of California, San Francisco, US; the University of North Carolina, Chapel Hill, US; Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany; and Stanford University, US, announced their discovery of a “biased agonist” for the MOR. The compound shifted the receptor’s signaling toward the analgesia-associated G protein pathway, and away from the side effect-associated beta-arrestin pathway. Two months later, a separate group at The Scripps Research Institute, Jupiter, US, revealed an additional biased agonist, this time for the kappa opioid receptor (see related PRF stories here and here).
Rather than try to bias receptor signaling, Ko, Zaveri, and others have taken a different approach. In 2012, Ko and his colleagues found that, when combined, small doses of the MOR partial agonist buprenorphine and a nociceptin receptor agonist acted synergistically, producing an antinociceptive effect that was greater than expected (Cremeans et al., 2012). And, “at those doses, they didn’t produce any [of the measured] side effects,” said Ko. Perhaps a dual agonist would do the same, he thought.
Ko eventually found evidence to support his idea. In a 2016 study, his lab showed that the nociceptin/mu agonist BU08028 could blunt pain in primates without affecting the animals’ breathing, body temperature, heart rate, or reward circuits (Ding et al., 2016). “But this compound also has some binding affinity for other opioid receptor subtypes,” said Ko.
So, to develop a true dual agonist, Zaveri’s group began with a candidate they selected from a library of nociceptin ligands. By tweaking the compound’s structure, they generated five analogs, including AT-121. Unlike the other variants, AT-121 showed partial activity at nociceptin and mu opioid receptors, while having little affinity for the delta and kappa subtypes—it was a bifunctional opioid.
Enter Ko, whose group next tested the new compound in 15 male and female rhesus macaque monkeys. “Because we know there are differences in nociceptin receptor function between rodents and primates, and because we already had studied nociceptin-related compounds in nonhuman primates, we wanted to jump right into this animal model,” he said.
With the right dose, lead authors Huiping Ding, Norikazu Kiguchi, and their colleagues found that they could completely block acute nociceptive responses in a warm water tail-withdrawal assay for three hours. And, following capsaicin treatment, this dose almost entirely relieved the animals’ thermal allodynia. It seemed, then, that AT-121 was an effective analgesic.
A safer opioid?
Yet, compared to opioids such as morphine and heroin, the compound carried fewer risks. A single dose left breathing untouched, even when increased by a factor of 10. Over time, AT-121 led neither to hyperalgesia (measured after one day) nor to tolerance (measured after four weeks). And while the MOR antagonist naltrexone precipitated withdrawal in morphine-treated animals, a combination of naltrexone and a nociceptin antagonist did not trigger withdrawal after multiple doses of AT-121.
As for the compound’s reinforcing properties, the animals self-administered AT-121 to the same extent as saline. Moreover, like buprenorphine and naltrexone, systemic administration of the compound decreased how much oxycodone animals self-administered. So AT-121 could interfere with the reinforcing properties of other opioids.
Ko envisions AT-121 potentially being used like buprenorphine, a medication prescribed for pain and opioid addiction. “But this drug might be slightly better, because buprenorphine can still be abused,” he said.
“This is further confirmation of the hypothesis that you can use the synergy between the nociceptin and mu receptor to give some effective pain relief without promoting mu opioid side effects,” said Streicher. “This is not the first compound to do that, but it’s an impressive demonstration.”
Indeed, AT-121 in many ways resembles BU08028. Still, the two compounds might have key differences. In Ko’s 2016 study, the researchers did not test for the development of either tolerance or hyperalgesia. Additionally, “BU08028 looked like it had a hint of reinforcement,” said Streicher.
Then there’s cebranopadol, the first of this type of dual agonist to reach Phase 3 clinical trials. But unlike AT-121, it shows full activity at both nociceptin and mu opioid receptors. “Partial agonists, in general, are more tolerable,” said Ko. “Of course, in this study, we don’t have a side-by-side comparison, but I think scientists would expect full agonists to have a narrower therapeutic window compared to partial agonists.”
Despite the excitement surrounding the new compound, many questions still loom large. For example, “its efficacy at the mu receptor is fairly low, so I would want to see it tested in a more severe pain model,” said Streicher. That might warrant higher doses given over longer periods of time, perhaps allowing side effects to arise.
Going forward, Ko thinks the new opioid needs to be studied in a larger sample of primates, and in a variety of pain models.
Matthew Soleiman is a graduate student in the Department of History and Science Studies Program at the University of California, San Diego, US. Follow him on Twitter @MatthewSoleiman.
Image: Docking and binding interactions of bifunctional AT-121 in the mu opioid receptor active-state crystal structure, shown in cyan cartoon representation. The interacting amino acids are shown as cyan stick representations. Image and caption from Ding et al., Sci Transl Med. 2018 Aug 29; 10(456). Reprinted with permission from AAAS.
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