Chang Ying, Pi Weiyi, Ang Wei, Liu Yuanyuan, Li Chunlong, Zheng Jiajia, Xiong Li, Yang Tao, Luo Youfu
National Key Laboratory of Biotherapy, 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.
Bioorg Med Chem Lett. 2014 Apr 1;24(7):1672-6. doi: 10.1016/j.bmcl.2014.02.065. Epub 2014 Mar 5.
In this work, nineteen analogues of Agomelatine were readily synthesized through structural modification of the acetamide side-chain starting from the key common intermediate 2-(7-methoxynaphthalen-1-yl) ethanamine (3), which was prepared from commercially available compound 2-(7-methoxynaphthalen-1-yl) acetonitrile (2) in two steps. Corticosterone-induced PC12 pheochromocytoma cells phenotypic in vitro model was utilized to evaluate their potential antidepression activities. Imide compound 4a and acylamino carboxylic acid analogue 5b showed good protective effects on traumatic PC12 cells with protection rates of 34.2% and 23.2%, respectively. Further in vivo assessments in C57 mice FST (forced swim test) model demonstrated that compound 4a significantly reduced the immobility time of the tested subjects, indicating antidepressant-like activity. Preliminary toxicity assays conducted on human normal liver L02 cells and embryonic kidney 293 cells suggested a relatively low safety risk for compound 4a compared with the marketed drugs Agomelatine and Fluoxetine. The promising antidepressant-like efficacy of compound 4a, together with the relatively low toxicity to the normal tested cells and high liability of diffusion through the blood-brain barrier (BBB), presents us insights of exploration of me-better drug candidates of Agomelatine.
在本工作中，从关键的共同中间体2-(7-甲氧基萘-1-基)乙胺(3)开始，通过对乙酰胺侧链进行结构修饰，很容易地合成了19种阿戈美拉汀类似物，中间体3由市售化合物2-(7-甲氧基萘-1-基)乙腈(2)分两步制备。利用皮质酮诱导的PC12嗜铬细胞瘤细胞体外表型模型来评估它们潜在的抗抑郁活性。酰亚胺化合物4a和酰氨基羧酸类似物5b对受损伤的PC12细胞显示出良好的保护作用，保护率分别为34.2%和23.2%。在C57小鼠强迫游泳试验(FST)模型中进行的进一步体内评估表明，化合物4a显著缩短了受试对象的不动时间，表明具有类抗抑郁活性。对人正常肝L02细胞和胚胎肾293细胞进行的初步毒性试验表明，与市售药物阿戈美拉汀和氟西汀相比，化合物4a的安全风险相对较低。化合物4a有前景的类抗抑郁功效，加上对正常受试细胞相对较低的毒性以及通过血脑屏障(BBB)扩散的高可能性，为我们探索阿戈美拉汀的优化药物候选物提供了思路。
