| Autor: |
Kassick, Andrew J., Treat, Anny, Tomycz, Nestor, Feasel, Michael G., Kolber, Benedict J., Averick, Saadyah |
| Zdroj: |
MedChemComm; 2022, Vol. 13 Issue: 2 p175-182, 8p |
| Abstrakt: |
The recent widespread abuse of high potency synthetic opioids, such as fentanyl, presents a serious threat to individuals affected by substance use disorder. Synthetic opioids generally exhibit prolonged in vivocirculatory half-lives that can outlast the reversal effects of conventional naloxone-based overdose antidotes leading to a life-threatening relapse of opioid toxicity known as renarcotization. In this manuscript, we present our efforts to combat the threat of renarcotization by attempting to extend the half-life of traditional MOR antagonists through the design of novel, fluorinated 4,5-epoxymorphinans possessing increased lipophilicity. Analogues were prepared viaa concise synthetic strategy highlighted by decarboxylative Wittig olefination of the C6ketone to install a bioisosteric 1,1-difluoromethylene unit. C6-difluoromethylenated compounds successfully maintained in vitropotency against an EC90challenge of fentanyl and were predicted to have enhanced circulatory half-life compared to the current standard of care, naloxone. Subsequent in vivostudies demonstrated the effective blockade of fentanyl-induced anti-nociception in mice. |
| Databáze: |
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