Discovery, asymmetric synthesis and biological evaluation of new bisbenzylisoquinoline-orexin receptor antagonists for insomnia treatment

IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL
Jing Fang , Yang Wang , Jia He , Chengyu Ge , Yindi Zhang , Yufeng Liu , Yueping Jiang , Shao Liu
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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.

Abstract Image

Abstract Image

新型双苄基异喹啉-食欲素受体拮抗剂的发现、不对称合成及生物学评价
新的食欲素受体(OXR)拮抗剂的开发为解决临床对安全有效的抗失眠药物的迫切需求提供了一条重要途径。本课课组通过虚拟筛选发现,莲子碱(neferine)是一种从莲子属(Nelumbinis Plumula)中分离出来的双苄基异喹啉生物碱,对OXR具有预测的结合亲和力。本文报道了一种新的cur•Me2S/吡啶酸催化芳基化方法,用于不对称合成罂粟碱及其异构体。生物实验结果表明,(R,S)-neferine对OXR的拮抗活性优于suvorexant,结合亲和度为KD (OX1R) 0.68和(OX2R) 0.81 nM。体内药效学研究表明,(R,S)-neferine比daridorexant更有效地降低小鼠的自发活动,并显著改善失眠小鼠的睡眠。此外,(R,S)-neferine可以恢复因失眠引起的PER1和PER2的显著下调以及BMAL1的上调,并降低OX1R和OX2R的表达,从而改善核心昼夜节律障碍。(R,S)-烟碱具有良好的药代动力学(F = 63.7%)和安全性(LD50>500mg/kg),急性毒性试验中未观察到死亡和组织病理学变化。总的来说,这项工作强调了OXR拮抗剂(R,S)-neferine的治疗潜力,为治疗失眠提供了候选药物和可行的药物开发策略。
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来源期刊
CiteScore
11.70
自引率
9.00%
发文量
863
审稿时长
29 days
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.
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