Opioids—a class of drugs that are derived from or mimic the opium poppy plant—are used to treat severe and persistent pain. Many opioids are highly potent, which is in large part why they can also become highly addictive; as a result, opioids are a leading cause of injury-related death in the United States.1 Opioids function by binding to opioid receptors in brain cells, which initiates a complex set of chemical reactions that ultimately result in analgesia, or pain relief, and the side effects of opioids, which can include tolerance and addiction.2 However, by taking advantage of certain properties of the opioid signaling pathway, it may be possible to decouple the benefits of opioids from their risks. This reasoning informs research and development on biased opioids.
Researchers hope to develop powerful opioid analgesics without the risks of addiction, misuse, and overdose based on the principle of biased agonism. In biochemistry, an agonist is a substance that binds to and activates a receptor. Though one receptor may have multiple agonists, they might not activate the exact same signaling pathway. The opioid signaling pathway typically involves two main proteins: G protein and beta-arrestin.3 Some agonists, such as fentanyl, equally activate these two proteins and are said to be “balanced.”2 Other agonists, however, preferentially activate either G protein or beta-arrestin and are considered “biased.”
In 1999, a landmark study showed that mice lacking the beta-arrestin gene experienced analgesia through the opioid pathway when given morphine but significantly fewer side effects than mice with the beta-arrestin gene.4 This finding initiated a focus on opioid receptor agonists biased towards the G protein pathway, which is now a major strategy for the development of non-addictive opioids.5
The intravenous opioid TRV130 (also known as oliceridine) is a synthetic G protein-biased mu-opioid receptor agonist.6 Approved by the FDA in 2020, TRV130 showed promise in preclinical studies but failed to produce a significant degree of analgesia in patients who took the medication in clinical trials.5 Other natural and synthetic G protein-biased agonists have not yet undergone rigorous testing.
A 2021 study published in American Chemical Society Pharmacology & Translational Science identified several chemical G protein-biased agonists that may have more clinical benefit than TRV130.7 The investigators computationally simulated 430,000 instances of a chemical docking to an opioid receptor to construct a library of compounds that could potentially induce the opioid signaling pathway. After experimentation in cells, three compounds were found to be full agonists for mu-opioid receptors, which may be more effective than TRV130. Definitive evidence is pending further testing.
Another approach to biased opioid agonism attempts to identify agonists for other classes of opioid receptors, such as the delta-opioid receptor. Unlike mu-opioid receptors, activation of delta-opioid receptors does not induce some of the most common side effects of opioids, like respiratory depression and dependence (though these receptors are associated with other side effects, like convulsions).8 Though biased agonism at these receptors has not been extensively studied, there are several biased agonists that may interact with them.8 Further research into different aspects of biased opioid agonism will help accelerate the development of less harmful opioids and reduce the impact of the opioid crisis.
References
1. Understanding Drug Overdoses and Deaths | Drug Overdose | CDC Injury Center. https://archive.cdc.gov/www_cdc_gov/drugoverdose/epidemic/index.html (2023).
2. Che, T., Dwivedi-Agnihotri, H., Shukla, A. K. & Roth, B. L. Biased ligands at opioid receptors: Current status and future directions. Sci. Signal. 14, eaav0320 (2021), DOI: 10.1126/scisignal.aav0320
3. Bateman, J. T. & Levitt, E. S. Evaluation of G protein bias and β-arrestin 2 signaling in opioid-induced respiratory depression. Am. J. Physiol. – Cell Physiol. 321, C681–C683 (2021), DOI: 10.1152/ajpcell.00259.2021
4. Bohn, L. M. et al. Enhanced Morphine Analgesia in Mice Lacking β-Arrestin 2. Science 286, 2495–2498 (1999), DOI: 10.1126/science.286.5449.2495
5. Stanczyk, M. A. & Kandasamy, R. Biased agonism: the quest for the analgesic holy grail. PAIN Rep. 3, e650.
6. Lambert, D. & Calo, G. Approval of oliceridine (TRV130) for intravenous use in moderate to severe pain in adults. BJA Br. J. Anaesth. 125, e473–e474 (2020), DOI: 10.1097/PR9.0000000000000650
7. Lee, J. H. et al. Discovery of μ,δ-Opioid Receptor Dual-Biased Agonists That Overcome the Limitation of Prior Biased Agonists. ACS Pharmacol. Transl. Sci. 4, 1149–1160 (2021), DOI: 10.1021/acsptsci.1c00044
8. Kelly, E., Conibear, A. & Henderson, G. Biased Agonism: Lessons from Studies of Opioid Receptor Agonists. Annu. Rev. Pharmacol. Toxicol. 63, 491–515 (2023), DOI: 10.1146/annurev-pharmtox-052120-091058