A research study led by Susruta Majumdar, PhD, and his team, published in ACS Science Central on Wednesday, July 17, introduces a promising strategy for developing safer opioid medications. This innovative research could pave the way for pain relief options with a reduced risk of withdrawal and fatal overdose.
Opioids, while effective at managing pain, pose significant risks, including physical dependence and respiratory depression, which can be deadly in cases of overdose. Traditional attempts to mitigate these risks have focused on designing molecules that interact with the same active site on the opioid receptor as the body’s natural pain-relieving signals. However, these efforts have had limited success in reducing the adverse effects associated with opioid use.
“The traditional approaches have not adequately addressed the severe side effects of opioid use,” Majumdar explained. “Our research aims to shift this paradigm by targeting a previously less explored allosteric site on the opioid receptor.'”
In their recent study, Majumdar and team led by postdoctoral fellow Rohini Ople,
investigated compounds that bind to an alternative site on the opioid receptor that is responsive to sodium ions. This site offers a new target for drug design by targeting mobile waters, leading to precision control of efficacy while maintaining pain relief and minimizing harmful side effects.
Building on their previous work, the team identified a compound, C6 guano, capable of activating the opioid receptor via this alternative site. However, C6 guano faced a significant limitation: it could not cross the blood-brain barrier, a critical requirement for effective central pain relief. To overcome this barrier, the team synthesized and evaluated ten new compounds.
Among these, one compound, RO76 emerged as a promising candidate. Derived from fentanyl, RO76 not only demonstrated the ability to cross the blood-brain barrier but also exhibited pain suppression comparable to morphine in mouse models. Importantly, RO76 showed a significantly reduced impact on respiratory rates, indicating a lower risk of fatal respiratory depression. Additionally, treatment with RO76 resulted in fewer withdrawal symptoms compared to traditional opioids, suggesting a lower potential for dependence.
“The development of RO76 could be a breakthrough in pain management, as it offers the potential for effective pain relief with a markedly lower risk of withdrawal and fatal overdose,” Majumdar stated.
Furthermore, Majumdar’s team found that RO76 retained its pain-relieving efficacy when administered orally, highlighting its potential for development into an easily administered medication.
These findings represent a significant advancement and could revolutionize pain management, offering a much-needed solution to the side effects and dangers associated with current opioid medications.