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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. Monkeys that were pretreated with AT-121 before being exposed to oxycodone exhibited no signs of experiencing oxycodone reinforcement. The researchers also established that AT-121 may have potential as a treatment for opioid addiction.

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See full text description at end of article. (Right) Compared to morphine, AT-121 achieved equivalent amounts of pain suppression at doses about 100 times lower. Animals that received the highest AT-121 dose (0.03 mg/kg) left their tails in the water for 100 percent of the maximum immediately after the injection, and 40 percent of the maximum after 3 hours. AT-121 Suppresses Pain and Is More Potent Than Morphine (Left) Researchers injected rhesus monkeys with AT-121 and assessed pain suppression at five time points (0.5, 1, 2, 3, and 6 hours) post-injection.В They reported AT-121вЂ™s pain suppressing effect as the percentage of a maximum time interval (determined to avoid injury to the animals) animals left their tails in warm (50 вЃ°C) water before becoming uncomfortable and withdrawing them. 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.ДЇigure 2. In another experiment, AT-121 reduced heightened pain sensations like those that are sparked by hypersensitive pain fibers in some chronic pain conditions. To achieve the same level of pain suppression with morphine, a dose 100 times higher was required (see Figure 2). In one experiment, the researchers found that AT-121 at a dose of 0.03 mg/kg completely suppressed monkeysвЂ™ discomfort when their tails were placed in very warm (50 degrees C) water. 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. Mei-Chuan Ko, and colleagues at Wake Forest School of Medicine conducted preclinical tests of AT-121. Zaveri, this interaction with the NOP receptor enhances AT-121вЂ™s analgesic effect and blocks unwanted side effects often seen with current opioid medications.Дr. However, unlike those opioids, AT-121 also binds to another opioid receptor called the nociceptin/orphanin FQ peptide (NOP) receptor (see Figure 1). Like opioids such as morphine and oxycodone, AT-121 binds to the mu opioid receptor (MOR). Nurulain Zaveri and colleagues at Astraea Therapeutics used medicinal chemistry, computer modeling, and structure-based drug design to design and develop AT-121. S ee full text description at end of article.Дr. AT-121 is designed to interact with both receptors.

(Right) Similarly, AT-121 fits into a pocket formed by the protein coils of the NOP receptor (pink).

AT-121 Binds to Both the MOR and the NOP Receptor (Left) The AT-121 molecule (green) is nestled in between the protein coils of the MOR (teal).