PainRelief.com: What are the main findings?
Response: Using this insight, the collaborative team confirmed the new bitopic strategy for designing new, safer opioids. This study improved systemic activity of ligands by interacting indirectly with the sodium site through water molecules. This interaction led to lower efficacy activation of the opioid receptor linked to reduced opioid side effects. Confirming this, the researchers showed that an experimental “bitopic” opioid, suppresses pain with fewer side effects — most notably those linked to fatal overdoses.
PainRelief.com: What should readers take away from your report?
Response: The research team showed earlier that fentanyl could be made safer by modifying it into a bitopic drug; that is, one that interacts with a location inside the opioid receptor that typically responds to sodium ions. However, this modified drug could not pass the blood-brain barrier, limiting its usefulness. Seeking to make more useful versions while confirming the earlier mechanism, the researchers synthesized and evaluated 10 compounds whose chemistry might enable passage through the blood-brain barrier.
By capturing molecules in proximity of the activated opioid receptor, initial testing showed that compound RO76 produces a signal within cells that differs from those initiated by classic opioids like morphine. When comparing RO76’s efficacy to morphine in mice, RO76 appeared to suppress pain as effectively as morphine, even when given orally. Additionally, when comparing the opioids’ effects on the animals breathing rates, they found that RO76 slowed breathing far less, suggesting it may be less deadly than morphine. Likewise, when they gave the mice an opioid-blocking medication, those chronically taking RO76 experienced fewer withdrawal symptoms. Importantly, biophysical measures with a method called cryo-EM show the interaction of RO76 with the internal location responding to sodium ions, confirming the strategy of using the new mechanistic insights.
The researchers write that these results with RO76 suggest the potential for development as an oral medication. Moreover, their results further validate the strategy of developing bitopic opioid drugs as safer painkillers.
The work is described in an article “Signaling modulation mediated by ligand water interactions with sodium site at μOR” published this week in the journal ACS Central Science by authors Ople RS, Ramos-Gonzalez N, Li Q, Sobecks BL, Aydin D, Powers AS, Faouzi A, Polanco BJ, Bernhard SM, Appourchaux K, Sribhashyam S, Eans SO, Tsai BA, Dror RO, Varga BR, Wang H, Huttenhain R, McLaughlin JP, Majumdar S.
PainRelief.com: What recommendations do you have for future research as a result of this study?
Response: The need to both treat pain and overcome the opioid epidemic it fuels remain urgent. While RO76 is a promising candidate, further research is needed to advance RO76 through testing for safety, toxicity and efficacy before attempting clinical trials. Moreover, further application of the strategy to generate safer bitopic medications for many receptors – not just opioid receptors – may lead to the improvement of existing medications with safer profiles of use.
Disclosures: Two of the study authors acknowledge financial interests with bio-pharmaceutical companies, although these interests did not support the current work. The authors gratefully acknowledge funding from the National Institutes of Health, and the Pharmaceutical Research and Manufacturers of America for Postdoctoral Fellowships, in support of this project.
Citation: ACS Cent. Sci. 2024, XXXX, XXX, XXX-XXX
Publication Date:July 17, 2024
https://doi.org/10.1021/acscentsci.4c00525
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Last Updated on July 19, 2024 by PainRelief.com