Synthesis and biological evaluation of magnolol derivatives as melatonergic receptor agonists with potential use in depression
Synthesis and biological evaluation of magnolol derivatives as melatonergic receptor agonists with potential use in depression
复制标题
厚朴酚衍生物作为褪黑激素受体激动剂的合成和生物学评价，具有治疗抑郁症的潜在用途
DOI：
10.1016/j.ejmech.2018.07.027
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发表时间：
2018-08-05
影响因子：
6.7
通讯作者：
Chen, Ji-Jun
中科院分区：
文献类型：
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作者：
Yang, Tong-Hua;Ma, Yun-Bao;Chen, Ji-Jun
抑郁症与全世界的高死亡率和发病率有关。通过我们的随机筛选，首先发现合成了 23 种厚朴酚衍生物，然后对其抗抑郁潜力进行了体外和体内评估。化合物7c被发现是最有前途的化合物，其对MT1和MT2受体的EC50值分别为396.5和383.0μM。此外，我们还进行了体内实验来证实化合物7c的有效性和安全性；该化合物被发现具有口服生物利用度且高效，可显着减少抑郁症小鼠模型的不动时间（强迫游泳试验和悬尾试验）；通过测定其对小鼠不同脑区单胺类神经递质及其代谢物水平的影响，探讨其作用机制；急性毒性研究表明，7c的50%致死剂量（LD50）高于2000 mg/kg，p. o。共鉴定出7c的25种代谢物，其中5种处于I期代谢物，20种处于II期代谢物。总而言之，这些结果表明厚朴酚衍生物 7c 是一种有前途的先导化合物，可用于开发新型化学类抗抑郁药物。 (C) 2018 Elsevier Masson SAS。版权所有。
Depression is associated with high mortality and morbidity rates worldwide. By our random screening, it was first revealed that 23 magnolol derivatives were synthesized followed by in vitro and in vivo evaluation of their antidepressive potential. Compound 7c was found to be the most promising compound, with EC50 values of 396.5 and 383.0 mu M agitating on MT1 and MT2 receptors, respectively. Additionally, we carried out in vivo experiments to confirm the efficacy and safety of compound 7c; the compound was found to be orally bioavailable and highly effective, leading to a significant reduction of immobility time in a mouse model of depression (forced swimming test and tail suspension test); the acting mechanism was explored by determining its effect on the levels of monoamine neurotransmitters and their metabolites in different mice brain regions; the acute toxicity study showed that the 50% lethal dose (LD50) of 7c was higher than 2000 mg/kg, p. o. A total of 25 metabolites of 7c were identified, including 5 metabolites in phase I and 20 metabolites in phase II. Altogether, these results indicate that magnolol derivative 7c is a promising lead compound for the development of a new chemical class of antidepressant drugs. (C) 2018 Elsevier Masson SAS. All rights reserved.