Total synthesis and biological activity of carbamorphine: O-to-CH2 replacement in the E-ring of the morphine core structure

• 成果类型: Article
• 署名作者: Akiyama, Sota; Ople, Rohini S.; Kremsmair, Alexander; Ramos-Gonzalez, Nokomis; Nedungadan, Thomas; Kennedy, Brandon J.; Appourchaux, Kevin; Eans, Shainnel O.; Tsai, Bowen A.; Kraml, Christina; Huang, Xi-Ping; McLaughlin, Jay P.; Majumdar, Susruta; Sarpong, Richmond
• 署名单位: University of California System; University of California Berkeley; Washington University (WUSTL); Washington University (WUSTL); University of Health Sciences & Pharmacy in St. Louis; Princeton University; State University System of Florida; University of Florida; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10999
• DOI: 10.1073/pnas.2425438122
• 发表日期: 2025-07-08
• 关键词: mu-opioid-receptor; alkaloids; antinociception; activation; chemistry; thebaine; naloxone; fentanyl; efficacy; oxalates

摘要

Morphine is a mu- opioid receptor (MOR) agonist and potent analgesic. However, it displays several side effects including respiratory depression and addiction. Here, we show that a single heavy atom replacement in the morphine core structure (O to CH2 exchange in the E-ring) prepared through a 15-step total synthesis displays a different pharmacological profile. The total synthesis features an intramolecular inverse electron-demand Diels-Alder cycloaddition and a stereoselective Giese radical addition to construct a quaternary carbon center. Unlike morphine, where the (-)-morphine enantiomer binds the MOR, both enantiomers of this carba variant, which we have named carbamorphine, possess activity as agonists of the MOR. Cell-based functional assays show that (+)-carbamorphine shows reduced G-protein as well as beta- arrestin efficacy at the MOR. In mouse behavioral assays, (+)-carbamorphine exhibits MOR-selective antinociception while showing reduced respiratory depression and a lack of conditioned place preference at supratherapeutic doses. Overall, through a net single-atom change (i.e., O to CH2) in the morphine framework, different pharmacological profiles have been realized. This work provides a basis for additional syntheses and the study of morphine analogs that incorporate atom changes in the core framework.