Jing Fang , Yang Wang , Jia He , Chengyu Ge , Yindi Zhang , Yufeng Liu , Yueping Jiang , Shao Liu
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引用次数: 0
Abstract
The development of new orexin receptor (OXR) antagonists represents a crucial avenue for addressing the urgent need for safe and effective anti-insomnia drugs in clinical practice. Our group discovered neferine, a bisbenzylisoquinoline alkaloid isolated from Nelumbinis Plumula, exhibited a predicted binding affinity for OXR through virtual screening. Herein, we report the asymmetric synthesis of neferine and its isomers using a novel CuBr•Me2S/picolinic acid-catalyzed arylation method. Biological assay results indicated that (R,S)-neferine demonstrated superior OXR antagonistic activity than suvorexant, with good binding affinities of KD (OX1R) 0.68 and (OX2R) 0.81 nM. In vivo pharmacodynamic studies showed that (R,S)-neferine reduced spontaneous activities in mice more effectively than daridorexant and significantly improved sleep in insomnia mice. Furthermore, (R,S)-neferine can restore the significant downregulation of PER1 and PER2, along with the upregulation of BMAL1 caused by insomnia, and decrease the expression of OX1R and OX2R, thereby improving core circadian rhythm disorders. (R,S)-neferine carried outstanding pharmacokinetic (F = 63.7 %) and safety profiles (LD50 > 500 mg/kg), no mortality or histopathological changes were observed during the acute toxicity test. Overall, this work highlights the therapeutic potential of the OXR antagonist (R,S)-neferine, providing candidates and viable drug development strategies for the treatment of insomnia.
期刊介绍:
The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers.
A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.