Synthesis and biological evaluation of novel isobenzofuran-1(3H)-one derivatives as antidepressant agents

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-16 DOI:10.1016/j.bmc.2024.117941

Liu Tao , Chuanjie Yao , Sijie Wang , Yuying Ye , Zhengchao Tu , Xiaojian Jiang , Lipeng Xu , Luchen Shan , Zheng Liu , Pei Yu

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Abstract

A series of novel isobenzofuran-1(3H)-one derivatives were designed and synthesized as antidepressants. Firstly, the serotonin reuptake inhibition of these compounds was tested in vitro, and most of them exhibited activity. Particularly, compounds 9d, 10a, and 10c demonstrated superior inhibitory effects and possibly avoided addiction via the μ-opioid receptor and CCK-B receptor. Secondly, the antidepressant effect of compound 10a was evaluated using chronic restraint stress (CRS)-induced mice. The results showed that compound 10a significantly improved CRS-induced depression-like behavior by increasing the neurotransmitters 5-HT in the cortex and THP2 expression in the hippocampus. Thirdly, compound 10a was further investigated and found to enhance CRS-induced hippocampal neuron damage recovery and elevate the expression of synaptic-associated proteins such as BDNF, TrkB, PSD95, and Spinophilin in CRS-induced mice. These findings suggested that novel isobenzofuran-1(3H)-one derivative showed efficacy in treating depression, with compound 10a emerging as a potential lead compound warranting further investigation.

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作为抗抑郁剂的新型异苯并呋喃-1(3H)-酮衍生物的合成和生物学评价。

研究人员设计并合成了一系列新型异苯并呋喃-1(3H)-酮衍生物作为抗抑郁药物。首先，对这些化合物的血清素再摄取抑制作用进行了体外测试，结果表明大多数化合物都具有活性。特别是化合物 9d、10a 和 10c 表现出了卓越的抑制作用，并可能避免了通过μ-阿片受体和 CCK-B 受体上瘾。其次，利用慢性束缚应激（CRS）诱导的小鼠评估了化合物 10a 的抗抑郁作用。结果表明，化合物 10a 通过增加大脑皮层中神经递质 5-HT 和海马中 THP2 的表达，明显改善了 CRS 诱导的抑郁样行为。第三，进一步研究发现，化合物 10a 能增强 CRS 诱导的海马神经元损伤恢复，并提高 CRS 诱导的小鼠突触相关蛋白（如 BDNF、TrkB、PSD95 和 Spinophilin）的表达。这些研究结果表明，新型异苯并呋喃-1(3H)-酮衍生物具有治疗抑郁症的疗效，其中化合物 10a 是一种潜在的先导化合物，值得进一步研究。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.