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Researchers have developed a bifunctional compound, known as AT-121, that possesses morphine-like analgesic effects and suppresses opioid dependency.1 The study, conducted in non-human primates, was recently published in the journal Science Translational Medicine.



According to the National Institute on Drug Abuse, >115 people in the US die each day from overdosing on opioids – AT-121 holds promise as a means for treating prescription opioid abuse – helping to combat the opioid crisis.



“The opioids that are most effective and widely used such as morphine, oxycodone, hydrocodone, and even buprenorphine act through the mu opioid receptor (MOP). Unfortunately, their pain relief action comes with the risk of opioid side effects, which are on-target effects,” comments Nurulain T. Zaveri, corresponding author of the study.



The team began exploring the pharmacology of another receptor known as the nociception opioid peptide receptor (NOP). Previous studies have demonstrated that NOP agonists can modulate the addictive properties of MOP agonists as well as their pain-relieving properties.2-5



The researchers sought to develop a bifunctional compound that could target both receptors, NOP and MOP, and in doing so they wanted to determine whether it could retain opioid-like pain relief properties – but without the side effects associated with existing opioid drugs.



Structure-based drug design and medicinal chemistry methods were used to develop and optimize AT-121, which targets both MOP and NOP. The researchers then investigated its therapeutic potential using non-human primates.



The study data demonstrated that AT-121:

provided pain relief in primates that was 100-fold higher compared to morphine,

lacked the rewarding features of other opioid drugs,

administered at high dose, did not cause motor impairment, respiratory depression or other abnormal physiologic changes,

did not cause withdrawal symptoms.1

"Our data shows that targeting the nociceptin opioid receptor not only dials down the addictive and other side-effects, it provides effective pain relief," explains Zaveri.



"The fact that this data was in non-human 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."



AT-121 is currently still undergoing preclinical investigation. Once the team have fully characterized the compound’s safety and toxicity profile in animal models, they intend to file an ‘Investigational New Drug’ application which will enable them to progress AT-121 into human trials.



References



1. Ding, H., et al. A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci Transl Med. (2018) Available at: http://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aar3483

2. Zaveri, N.T. The nociceptin/orphanin FQ receptor (NOP) as a target for drug abuse medications. Curr. Top. Med. Chem. 11, 1151–1156 (2011)

3. Lambert, D.G. The nociceptin/orphanin FQ receptor: A target with broad therapeutic potential. Nat. Rev. Drug Discov. 7, 694–710 (2008)

4. L. Toll, L., et al. Nociceptin/orphanin FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems. Pharmacol. Rev. 68, 419–457 (2016)

5. Calò, G, Guerrini, R. Medicinal chemistry, pharmacology, and biological actions of peptide ligands selective for the nociceptin/orphanin FQ receptor, in Research and Development of Opioid-Related Ligands, M. C. Ko, S. M. Husbands, Eds. (American Chemical Society, 2013), vol. ACS Symposium Series, chap. 15, pp. 275–325



