新型AMPA受体正向变构调节剂抗疲劳活性筛选  

Anti-fatigue activity screening of novel positive allosteric modulators on AMPA receptor

作　　者：陈瑶 马淑梅 梅其炳[1,2,3] 刘莉 

机构地区：[1]中国医药工业研究总院药理评价研究中心,上海200040 [2]上海市生物物质成药性评价专业技术服务平台,上海200437 [3]上海医药工业研究院创新药物与制药工艺国家重点实验室,上海200437

出　　处：《中国药理学通报》2018年第3期382-387,共6页Chinese Pharmacological Bulletin

基　　金：上海市生物物质成药性评价专业技术服务平台(No15DZ2291700)

摘　　要：目的寻找以AMPA(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)受体为靶点的新型抗疲劳化合物。方法以胡椒酸、3,4,5-三甲氧基苯甲酸、3,4-二甲氧基苯甲酸,这3个化合物分别作为母体结构,对苯甲酰胺的酰胺氮原子引入基团进行结构修饰,设计合成43个化合物,结构经1H-NMR确认。采用MTT法评价新化合物的细胞毒性,通过戊巴比妥钠镇静催眠实验进行中枢兴奋性筛选,最后采用小鼠负重游泳实验评价目标新化合物抗疲劳活性。结果化合物2j细胞毒性低,具有一定的中枢兴奋性与抗疲劳活性。结论化合物2j具有较好的抗疲劳作用,具有进一步开发潜力。Aim To explore the novel anti-fatigue agents targeting AMPA receptor. Methods Three benzoic acids of different methoxy substitutions were employed,including piperonylic acid,3,4,5-trimethoxy benzoic acid and 3,4-dimethoxy benzoic acid,which as mother nucleus and cyclic aliphatic amine or phenylpiperazine derivatives were introduced to modify the nitrogen atoms connecting to amino bonds. Forty-three compounds were synthesized and identified by1 HNMR. MTT assay,then pentobarbital induced hypnosis experiment and mice burden swimming experiment were applied respectively to evaluate the new synthesized compounds ＇ cytotoxicity,CNS excitability and anti-fatigue activity. Results Compound 2 j had low cytotoxicity,presenting certain central excitability and significant advantages on anti-fatigue. Conclusion The further development of compounds 2 j with good anti-fatigue activities could be cultivated in further study.

关 键 词：AMPA受体 苯甲酰胺类 细胞毒性 中枢兴奋性 负重游泳 抗疲劳 

分 类 号：R-332[医药卫生] R392.11