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

ABSTRACT: Morphine is a µ-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 sh

SUBMITTER: Akiyama S 

PROVIDER: S-EPMC12260398 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature