Design, synthesis, and biological evaluation of C-difluoromethylenated epoxymorphinan Mu opioid receptor antagonists.

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 circulatory 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 a concise synthetic strategy highlighted by decarboxylative Wittig olefination of the C ketone to install a bioisosteric 1,1-difluoromethylene unit. C-difluoromethylenated compounds successfully maintained potency against an EC challenge of fentanyl and were predicted to have enhanced circulatory half-life compared to the current standard of care, naloxone. Subsequent studies demonstrated the effective blockade of fentanyl-induced anti-nociception in mice.