Design, Syntheses, and Pharmacological Evaluations of Core Ring Expanded Fentanyl Analogues as Potential...

The escalating synthetic opioid crisis necessitates novel treatments, especially for fentanyl overdose. This study presents 84 ring-expanded fentanyl analogs, replacing its piperidine core with 4-azepane and 5-azocane structures. In vivo antagonism studies identified 15 compounds that effectively blocked synthetic opioid antinociception. Further dose-response analysis identified four potent antagonists (16, 46, 53, and 69) against both fentanyl and morphine. Notably, Compound 53 demonstrated the highest potency with AD₅₀ of 2.02 mg/kg against morphine and 4.02 mg/kg against fentanyl. Compound 53 exhibits a favorable pharmacokinetic profile, including moderate human metabolic stability, low efflux, and efficient, sustained CNS penetration, making it a promising centrally acting MOR antagonist candidate. Significantly, whole-body plethysmography confirmed that compound 53 reversed fentanyl-induced respiratory depression. These results suggest that expanding the core ring structure of fentanyl is a promising strategy to develop potent mu opioid receptor antagonists to inhibit both antinociception and respiratory depression offering potential solutions to fentanyl overdose.