This research shows:
- An experimental compound with a dual action at two opioid receptors may provide powerful pain relief without many of opioids' harmful side effects.
- The compound may also have potential as a treatment for opioid addiction.
A novel compound represents a potential advance toward the goal of nonaddicting analgesics that are at least as effective as opioids but without typical opioid liabilities. The new compound, called AT-121, may also have potential as a treatment alternative for opioid addiction.
Dr. Nurulain Zaveri and colleagues at Astraea Therapeutics used medicinal chemistry, computer modeling, and structure-based drug design to design and develop AT-121. Like opioids such as morphine and oxycodone, AT-121 binds to the mu opioid receptor (MOR). However, unlike those opioids, AT-121 also binds to another opioid receptor called the nociceptin/orphanin FQ peptide (NOP) receptor (see Figure 1). According to Dr. Zaveri, this interaction with the NOP receptor enhances AT-121’s analgesic effect and blocks unwanted side effects often seen with current opioid medications.
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Dr. Huiping Ding, Dr. Mei-Chuan Ko, and colleagues at Wake Forest School of Medicine conducted preclinical tests of AT-121. After confirming in vitro that AT-121 bound strongly to and activated both MOR and NOP receptors, the research team assessed its pain-suppressing efficacy. In one experiment, the researchers found that AT-121 at a dose of 0.03 mg/kg completely suppressed monkeys’ discomfort when their tails were placed in very warm (50 degrees C) water. To achieve the same level of pain suppression with morphine, a dose 100 times higher was required (see Figure 2). In another experiment, AT-121 reduced heightened pain sensations like those that are sparked by hypersensitive pain fibers in some chronic pain conditions. Moreover, monkeys were no more likely to self-administer AT-121 than saline, indicating that the compound was not reinforcing, and therefore unlikely to motivate misuse.
The researchers also established that AT-121 may have potential as a treatment for opioid addiction. Monkeys that were pretreated with AT-121 before being exposed to oxycodone exhibited no signs of experiencing oxycodone reinforcement.
In monkeys, even very high doses of AT-121 produced none of the harmful side effects associated with opioid drugs, such as altered respiration, heart rate, blood pressure, or body temperature; sedation; or motor impairment. Also, unlike traditional opioids, repeated treatment with AT-121 did not produce physical dependence, tolerance, or excessive pain sensitivity, which can occur with long-term opioid treatment.
In earlier research, Dr. Ko and colleagues identified a buprenorphine-like compound, BU08028, that acts on all four opioid receptors to deliver powerful, non-reinforcing pain relief. However, AT-121’s targeted activity at only the NOP and MOR receptors yielded the added advantage of an attractive profile for treatment of opioid use disorders.
Dr. Zaveri says, "A single bifunctional compound with activity at two targets, such as AT-121, is a better pharmaceutical strategy than combining different compounds, which may have different pharmacokinetic properties, rates of metabolism, and propensities for drug–drug interactions." Dr. Zaveri and colleagues are now conducting toxicology and safety tests of AT-121, after which they hope to proceed to clinical trials.
This study was supported by NIH grants DA032568, DA027811, DA042465, DA040104, and DA044775.
Ding, H., Kiguchi, N., Yasuda, D., et al. A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Science Translational Medicine 10(456): doi: 10.1126/scitranslmed.aar3483, 2018.
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NIDA. (2019, February 12). A Promising Alternative to Opioid Pain Medications. Retrieved from https://www.drugabuse.gov/news-events/nida-notes/2019/02/promising-alternative-to-opioid-pain-medications