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

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

  • J Med Chem. 2025 Nov 13;68(21):22170-22195. doi: 10.1021/acs.jmedchem.5c00528.
Abeje A Silte 1,  Ennian Li 1,  Balaji S Kale 1,  Logan Neel 1,  Neha Upadhyay 1,  Rachael Flammia 1,  Rui Lyu 1,  Celsey M St Onge 1,  Ahmed Reda 1,  Samuel Woodard 2,  James C Gillespie 2,  Daniel Kim 2,  Dana E Selley 2,  William L Dewey 2,  Piyusha P Pagare 1,  Yan Zhang 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, Virginia 23298, United States.
  • 2 Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States.
  • 3 Center for Drug Discovery, Virginia Commonwealth University, 800 East Leigh Street, Richmond, Virginia 23298, United States.
  • 4 Institute for Drug and Alcohol Studies, Virginia Commonwealth University, 203 East Cary Street, Richmond, Virginia 23298, United States.
PMID: 41178824 DOI: 10.1021/acs.jmedchem.5c00528
Abstract

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.

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