Design, synthesis, and biological evaluation of C6-difluoromethylenated epoxymorphinan Mu opioid receptor antagonists. Issue 2 (21st December 2021)

• Record Type: Journal Article
• Authors: Kassick, Andrew J.; Treat, Anny; Tomycz, Nestor; Feasel, Michael G.; Kolber, Benedict J.; Averick, Saadyah
• Is Part Of: RSC medicinal chemistry. Volume 13:Issue 2(2022)
• Page Start: 175
• Page End: 182
• Publication Date: 2021-12-21
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1039/d1md00285f
• Languages: English
• ISSNs: 2632-8682

Abstract

Abstract : C6 -difluoromethylenated epoxymorphinans were found to maintain in vitro potency against fentanyl and displayed effective in vivo blockade of fentanyl-induced anti-nociception in mice relative to the clinical opioid reversal agent naloxone. Abstract : 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 vivo 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 via a concise synthetic strategy highlighted by decarboxylative Wittig olefination of the C6 ketone to install a bioisosteric 1, 1-difluoromethylene unit. C6 -difluoromethylenated compounds successfully maintained in vitro potency against an EC90 challenge of fentanyl and were predicted to have enhanced circulatory half-life compared to the current standard of care, naloxone. Subsequent in vivo studies demonstrated the effective blockade of fentanyl-induced anti-nociception in mice.