Ang Wei, Chen Gong, Xiong Li, Chang Ying, Pi Weiyi, Liu Yuanyuan, Li Chunlong, Zheng Jiajia, Zhou Liangxue, Yang Bo, Deng Yong, Yang Shengyong, Luo Youfu, Wei Yuquan
State Key Laboratory of Biotherapy and Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China; Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
State Key Laboratory of Biotherapy and Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
Eur J Med Chem. 2014 Jul 23;82:263-73. doi: 10.1016/j.ejmech.2014.05.061. Epub 2014 May 27.
In this study, a series of novel naphthalene compounds were synthesized and screened for their antidepressant-like activities in vitro and in vivo. Their values for two descriptors (ClogP, tPSA) of the blood-brain barrier (BBB) were calculated for early assessment of the central nervous system (CNS) drug-likeness. Seven of them (6d, 6i, 6k, 6o, 6p, 6s and 6t) demonstrated potential protective effects on corticosterone-induced lesion of PC12 cells although they cannot repair the irreversible oxidant injury to PC12 cells by hydrogen peroxide. Compounds with promising neurorestorative activities (6k, 6o and 6p) were further evaluated for their in vivo effects by forced swim test (FST) and open field test (OFT) in C57 mice models. The FST results showed that compounds 6k, 6o and 6p remarkably reduced the immobility time of the tested mice. Among them, compound 6k was the most potent one, much more effective than Agomelatine and comparable to Fluoxetine. The OFT results showed that mice treated with compound 6k traveled a longer distance than those treated with Agomelatine or Fluoxetine, indicating a better general locomotor activity. The paper also proposed a possible binding mode of compound 6k with glucocorticoid receptor by docking study. The in vitro cytotoxicity data on HEK293 and L02 cells suggested compound 6k to be a promising antidepressant candidate for subsequent investigation.
在本研究中，合成了一系列新型萘化合物，并在体外和体内对其抗抑郁样活性进行了筛选。计算了它们血脑屏障（BBB）的两个描述符（ClogP、tPSA）的值，以便早期评估中枢神经系统（CNS）类药物性质。其中七种化合物（6d、6i、6k、6o、6p、6s和6t）对皮质酮诱导的PC12细胞损伤显示出潜在的保护作用，尽管它们无法修复过氧化氢对PC12细胞造成的不可逆氧化损伤。通过强迫游泳试验（FST）和旷场试验（OFT）在C57小鼠模型中进一步评估了具有良好神经修复活性的化合物（6k、6o和6p）的体内作用。FST结果表明，化合物6k、6o和6p显著缩短了受试小鼠的不动时间。其中，化合物6k活性最强，比阿戈美拉汀更有效，与氟西汀相当。OFT结果表明，用化合物6k处理的小鼠比用阿戈美拉汀或氟西汀处理的小鼠移动距离更长，表明其总体运动活性更好。本文还通过对接研究提出了化合物6k与糖皮质激素受体可能的结合模式。关于HEK293和L02细胞的体外细胞毒性数据表明，化合物6k是后续研究中一个有前景的抗抑郁候选物。
