纳曲酮
化学
吗啡
上瘾
药理学
麻醉剂拮抗剂
麻醉剂拮抗剂
类阿片
(+)-纳洛酮
神经科学
生物化学
心理学
受体
医学
作者
Jingwei Gao,Cong Lin,Cong Zhang,Xiaozheng Zhang,Yibo Wang,Han Xu,Tianshu Zhang,Hao‐Hong Li,Hongshuang Wang,Xiaohui Wang
标识
DOI:10.1021/acs.jmedchem.3c02316
摘要
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 (1) and (+)-14-hydroxymorphinone (3). These precursors exhibited TLR4 antagonistic activities 100 times stronger than (+)-naltrexone, particularly inhibiting the TLR4–TRIF pathway. In vivo 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, 3 displayed a longer half-life and higher oral bioavailability than 1. Overall, this research optimized (+)-naltrexone synthesis and identified its precursors as potent TLR4 antagonists, offering potential treatments for morphine addiction.
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