2-芳基咪唑并[1,2-a]吡啶-3-乙酰胺衍生物的合成与抗焦虑活性研究

Synthesis and anxiolytic effects of 2-aryl imidazo[1,2-a]pyridine-3-acetamide derivatives

目的寻找水溶性较好、抗焦虑活性较强的新型化合物。方法设计合成2-芳基咪唑并[1,2-a]吡啶-3-乙酰胺类化合物,通过体外苯二氮受体竞争结合实验及小鼠高架迷宫行为实验,评价化合物的体内外抗焦虑活性,分析化合物的构效关系。结果与结论共合成28个新型化合物,通过1H-NMR和MS确证其结构,其中I8和I10水溶性良好。苯二氮受体竞争结合实验结果表明,化合物Ⅰ1、Ⅰ8、Ⅰ10、Ⅰ13、Ⅰ19与苯二氮受体的亲和力与阳性对照药物Ro5-4864相当,在浓度为100nmol/L时,其对放射性配体与受体结合的抑制率分别为87%、89%、85%、89%和76%,而Ro5-4864为82%。对水溶性及活性均较好的化合物Ⅰ和Ⅰ进行小鼠抗焦虑活性评价结果表明,其具有明显的体内抗焦虑作用。

Objective To search for new compounds with better water-solubility and higher antianxiety activities.Methods A series of 2-arylimidazo[1,2-a]pyridine-3-acetamide derivitives were designed and synthesized.The anxiolytic activities were evaluated by BZDR competitive binding assay in vitro and the elevated-plus maze test in mice,the structure-activity relationship（SAR） has been studied.Results and Conclusion Twenty-eight new compounds have been synthesized.Their structures were confirmed by 1H NMR and MS.According to the results of BZDR affinity test,compoundsⅠ1,Ⅰ8,Ⅰ10,Ⅰ13,Ⅰ19 showed as good affinity as the positive control（Ro5-4864）.The corresponding inhibition was 87%,89%,85%,89% and 76% respectively at the concentration of 100 nmol/L,while that of Ro5-4864 was 82%.Ⅰ8 andⅠ10,which display better water-solubility and better BZDR affinity in vitro,show significant antianxiety effects in vivo.