BnOCPA for Analgesia: Potential Non-Addictive Compound 

Prescribing pain medications remains a complex topic in the medical field due to the high incidence of addiction associated with many analgesics (1). Although commonly prescribed to relieve chronic pain or ease postoperative discomfort, opioids such as oxycodone and hydrocodone exhibit highly addictive properties, such as the ability to induce tolerance, changes in the neurobiology of the brainstem, and dysregulation of norepinephrine production (2). In the United States, approximately 9.7 million people misuse prescription pain relievers every year, resulting in tens of thousands of hospital visits and deaths, primarily due to cardiorespiratory depression (3). As opioid overdoses continue to increase at an alarming rate — from 21,000 deaths in 2010 to more than 68,000 in 2020 (4) — researchers have begun to search for new non-opioid analgesics that retain the same power to relieve pain without the addictive characteristics and heightened risk of death from cardiorespiratory depression. Although they remain at an early stage in the research process, scientists at the University of Warwick have identified a novel molecular compound that may fulfill these analgesia requirements: benzyloxy-cyclopentyladenosine, or BnOCPA (5). 

Originally intended as a potential treatment for glaucoma, BnOCPA is a potent, highly selective derivative of adenosine (5). In contrast to typical opiate analgesics, which operate as adenosine 1 (A1R) agonists that activate G proteins on cells throughout the body (6), BnOCPA is a selective A1R agonist, meaning that it does not activate all of the same receptors. Specifically, BnOCPA only activates one type of G protein — GoB, expressed at high concentrations in the brain — while typical analgesics activate both GoB and GoA, which is expressed at high concentrations in the heart (5, 7). Therefore, by binding to a select subfamily of adenosine receptors, BnOCPA does not produce cellular hyperpolarization in the heart that is associated with the cardiorespiratory depression and sedation produced by typical A1R agonists while still inducing analgesia (5). To assess the efficacy of BnOCPA, the team compared the effects of the compound with other analgesics in mice and found that BnOCPA did not reduce motor coordination or cause oversedation, but significantly reduce reactions that indicated pain (5). Additionally, they demonstrated that the compound did not change the heart rate or blood pressure of the mice, even when the dose was doubled or tripled, due to the lack of effect on GoA proteins (5). Thus, BnOCPA provided analgesia without negatively affecting the cardiovascular system or alertness of the mice (5).  

In the future, the team hopes to extend their findings to humans in clinical trials. Their results, derived from a compound intended to treat eye conditions, present significant inspiration for the future of pain medication research and the battle against opioid addiction. Additionally, the use of BnOCPA itself may provide a safer, non-addictive analgesic option. While the potential to create an A1R agonist that differentiates between GoA and GoB proteins has been hypothesized for decades (7), BnOCPA represents the first successful attempt at this selective activation (5). Therefore, the discovery of BnOCPA as a potentially effective and safe alternative to opioids highlights the power and possibility of creating specific G-protein coupled receptor (GCPR) targets to circumvent the short-term and long-term adverse effects of analgesics.  

References 

1: Stein, C. (2018). New concepts in opioid analgesia. Expert Opinion in Investigational Drugs, vol. 27(10). DOI: 10.1080/13543784.2018.1516204. 

2: Kosten, T. and George, T. (2002). The neurobiology of opioid dependence: implications for treatment. Science and Practice Perspectives, vol. 1(1). DOI: 10.1151/spp021113. 

3: Substance Abuse and Mental Health Services Administration (2020). Key substance use and mental health indicators in the United States: results from the 2019 national survey on drug use and health. United States Department of Health and Human Services. Report. URL: https://www.samhsa.gov/data/sites/default/files/reports/rpt29393/2019NSDUHFFRPDFWHTML/2019NSDUHFFR1PDFW090120.pdf.  

4: United States National Institute on Drug Abuse (2021). Overdose death rates. Center for Disease Control and Prevention WONDER Database. Data brief. URL: https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates.  

5: Wall, M., Hill, E., Huckstepp, R., Barkan, K., Deganutti, G., Leuenberger, M., Preti, B., Winfield, I., Carvalho, S., Suchankova, A., Wei, H., Safitri, D., Huang, X., Imlach, W., La Manche, C., Dean, E., Hume, C., Hayward, S., Oliver, J., Zhao, F., Spanswick, D., Reynolds, C., Lochner, M., Ladds, G. and Frenguelli, B. (2022). Selective activation of GɑoB by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression. Nature Communications, vol. 13. DOI: 10.1038/s41467-022-31652-2.  

6: Jung, S., Peyton, L., Essa, H. and Choi, D. (2022). Adenosine receptors: emerging non-opioids targets for pain medications. Neurobiology of Pain, vol. 11. DOI: 10.1016/j.ynpai.2022.100087.  

7: Asano, T., Morishito, R. and Kato, K. (1992). Two forms of G(o) type G proteins: identification and distribution in various rat tissues and cloned cells. Journal of Neurochemistry, vol. 58(6). DOI: 10.1111/j.1471-4159.1992.tb10961.x.