Design, Syntheses, and Pharmacological Evaluations of Core Ring Expanded Fentanyl Analogues as Potential Counteracting Agents Against Fentanyl Induced Respiratory Depression

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. <i>In vivo</i> antagonism studies identified 15 compounds that effectively blocked synthetic opioid antinociception. Further dose-response analysis identified four potent antagonists (<b>16</b>, <b>46</b>, <b>53</b>, and <b>69</b>) against both fentanyl and morphine. Notably, Compound <b>53</b> demonstrated the highest potency with AD₅₀ of 2.02 mg/kg against morphine and 4.02 mg/kg against fentanyl. Compound <b>53</b> 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 <b>53</b> 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.