2. Academic Validation
  3. Investigating the Landscape of C6-Azaindole Side Chain on the Epoxymorphinan Skeleton via the Nitrogen Walk Concept: A Strategy to Enhance Drug-Like Properties

Investigating the Landscape of C6-Azaindole Side Chain on the Epoxymorphinan Skeleton via the Nitrogen Walk Concept: A Strategy to Enhance Drug-Like Properties

  • J Med Chem. 2026 Feb 12;69(3):2330-2348. doi: 10.1021/acs.jmedchem.5c02175.
Logan Neel 1 2,  Hongguang Ma 1,  Ahmed Reda 1,  Mengchu Li 1,  Rachael Flammia 1,  Samuel Woodard 2,  James C Gillespie 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 E Leigh Street, Richmond, Virginia 23298, United States.
  • 2 Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States.
  • 3 Center for Drug Discovery, Virginia Commonwealth University, 800 E 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: 41571452 DOI: 10.1021/acs.jmedchem.5c02175
Abstract

Opioid use disorder (OUD) affects 2.1 million people in the U.S., and current treatments have significant limitations. Therefore, there is a critical need for novel, selective, potent, and reversible mu Opioid Receptor (MOR) antagonists for OUD treatment. The "message-address" concept applied to the naltrexone skeleton keeps the epoxymorphinan core (message) consistent while modifying the C-6 substituent (address). This approach led to the development of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(indole-7-carboxamido)morphinan (NAN). In this study, we have designed and evaluated NAN analogues to enhance their pharmacological properties by applying the "nitrogen-walk" concept, i.e., replacing each CH group with a nitrogen atom on the indole ring sequentially while exploring different attachment positions onto the azaindole ring. A total of 36 analogues were synthesized and characterized. Competitive binding assays and functional activity studies identified eight potential MOR antagonists, with compound 7 showing the highest potency in a mouse antinociception model and inducing fewer withdrawal symptoms than naloxone.

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