新型AMPA受体正向变构调节剂抗疲劳活性筛选

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1 H-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 a-gents targeting AMPA receptor. Methods Three ben-zoic acids of different methoxy substitutions were em-ployed, including piperonylic acid, 3,4,5-trimethoxy benzoic acid and 3,4-dimethoxy benzoic acid, which as mother nucleus and cyclic aliphatic amine or pheny-lpiperazine derivatives were introduced to modify the nitrogen atoms connecting to amino bonds. Forty-three compounds were synthesized and identified by 1 H-NMR. MTT assay, then pentobarbital induced hypno-sis experiment and mice burden swimming experiment were applied respectively to evaluate the new synthesized compounds’ cytotoxicity, CNS excitability and anti-fatigue activity. Results Compound 2j had low cytotoxicity,presenting certain central excitability and significant advantages on anti-fatigue. Conclusion The further development of compounds 2j with good anti-fatigue activities could be cultivated in further study.