兼具抗氧化和γ-氨基丁酸增强活性的多功能抗脑卒中化合物

Multifunctional anti-stroke compounds with both antioxidant andγ-aminobutyric acid enhancing activity

目的:合成具有抗氧化和γ-氨基丁酸(γ-aminobutyric acid,GABA)增强活性的神经保护试剂并测试其抗脑卒中的神经保护作用。方法:从不同取代的酚出发合成依达拉奉的类似物,用1,1-二苯基-2-苦肼基(1,1-diphenyl-2-picryhydrazyl,DPPH)法测试化合物的抗氧化活性,用膜片钳技术测试化合物的GABA活性,并用大脑中动脉栓塞(middle cerebral artery occlusion,MCAO)模型测试化合物的神经保护作用。结果:合成了3’,5’-二异丙基-4’-羟基依达拉奉(6a)和3’-甲基-5’-叔丁基-4’-羟基依达拉奉(6b),两个化合物都显示了良好的体外抗氧化活性,在MCAO模型上两个化合物都显示了比依达拉奉更强的神经保护作用;电生理实验表明,化合物6b在低浓度下显示GABA增强活性,在高浓度下显示直接的GABAR激动活性。结论:基于依达拉奉的分子骨架,成功构建了同时具有抗氧化活性和GABA增强活性的新型神经保护试剂。

Objective:This study aims to synthesize multifunctional neuroprotective agent with antioxidant andγ-aminobutyric acid(GABA)activity and test their neuroprotective activity against stroke.Methods:The edaravone analogues were synthesized from phenols with distinct substitutes;the antioxidant activity was determined by 1,1-diphenyl-2-picryhydrazyl(DPPH)free radical scavenging activity;the GABA activity was evaluated by patch clamp,and the neuroprotective effect of the compounds was tested by MCAO model in rats.Results:The 3′,5′-Diisopropyl-4′-hydroxyedaravone(6a)and 3′-methyl-5′-tert-butyl-4′-hydroxy-edaravone(6b)were successfully synthesized,both compounds showed good in vitro antioxidant activity and stronger neuroprotection than edaravone on the MCAO model;electrophysiological experiments showed that compound 6b hod GABA enhancement activity at low concentration and direct GABAR agonistic activity at high concentration.Conclusion:Based on the molecular framework of edaravone,two new neuroprotecting agents with both antioxidant activity and GABA activity were successfully constructed.