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Papers of the Week

Papers: 3 Feb 2024 - 9 Feb 2024

2024 Feb 02

J Med Chem


Exploring the Function of (+)-Naltrexone Precursors: Their Activity as TLR4 Antagonists and Potential in Treating Morphine Addiction.


Gao J, Lin C, Zhang C, Zhang X, Wang Y, Xu H, Zhang T, Li H, Wang H, Wang X


Disruptions in the toll-like receptor 4 (TLR4) signaling pathway are linked to chronic inflammation, neuropathic pain, and drug addiction. (+)-Naltrexone, an opioid-derived TLR4 antagonist with a (+)-isomer configuration, does not interact with classical opioid receptors and has moderate blood-brain barrier permeability. Herein, we developed a concise 10-step synthesis for (+)-naltrexone and explored its precursors, (+)-14-hydroxycodeinone () and (+)-14-hydroxymorphinone (). These precursors exhibited TLR4 antagonistic activities 100 times stronger than (+)-naltrexone, particularly inhibiting the TLR4-TRIF pathway. studies showed that these precursors effectively reduced behavioral effects of morphine, like sensitization and conditioned place preference by suppressing microglial activation and TNF-α expression in the medial prefrontal cortex and ventral tegmental area. Additionally, displayed a longer half-life and higher oral bioavailability than . Overall, this research optimized (+)-naltrexone synthesis and identified its precursors as potent TLR4 antagonists, offering potential treatments for morphine addiction.