选择性5-HT_(6)R激动剂10-甲氧麦角碱衍生物的合成及其对大鼠前额叶皮层神经元电活动的影响  

10-Methoxy ergot derivatives as novel 5-HT_(6)R selective agonist:synthesis and the effect on prefrontal lobe function in rats

作　　者：张炼 宋卫强 方维臻 陆群 李杨 谭超 吴坚 赵昱 ZHANG Lian;SONG Wei-qiang;FANG Wei-zhen;LU Qun;LI Yang;TANG Chao;WU Jian;ZHAO Yu(Department of Chemical&Chemical engineering,School of life science and engineering,Southwest Jiaotong Universiy,Chengdu 611756,China;Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;Fuan Pharmaceutical Group Co.,Ltd.,Chongqing 401221,China;Yunnan Provincial Key Laboratory of Medical Insects and Spiders Resources for Development and Utilization,Dali University,Dali 671000,China)

机构地区：[1]西南交通大学生命科学与工程学院化学化工系,四川成都611756 [2]中国科学院上海药物研究所,上海201203 [3]福安药业股份有限公司,重庆401221 [4]大理大学药用特种昆虫开发国家地方联合工程研究中心,云南大理671000

出　　处：《中国药物化学杂志》2021年第12期955-962,共8页Chinese Journal of Medicinal Chemistry

基　　金：四川省科技支撑计划(2015FZ0016)。

摘　　要：目的设计合成10α-甲氧基麦角碱衍生物,以期得到具有选择性激动5-HT_(6)受体活性的麦角碱衍生物。方法以10α-甲氧基麦角醇为原料,对尼麦角林环C-8位侧链进行修饰改造,经氧化、缩醛化或酰胺化、酯化等反应合成得到5个新型10α-甲氧基麦角碱衍生物。采用Path Hunter^(■)β-Arrestin Assay高通量荧光受体结合实验方法,测试了这些化合物对5-HT受体的作用。结果合成获得5个新的10α-甲氧基麦角碱衍生物,其中化合物4对5-HT_(6)受体具有选择性激动的作用,全细胞膜片钳实验显示4具有前额叶的兴奋性递质过度投射作用。结论化合物4对5-HT_(6)受体具有选择性激动的作用,具有开发为改善认知功能的抗抑郁药物的潜在价值。Using 10α-methoxy ergoterol as starting material,the C-8 substituted chain of ergot skeleton was modified and five new derivatives of 10α-methoxy ergot alkaloids were synthesized via oxidation and amidation or esterification.The Path Hunter^(■) β-Arrestin Assay was used to test the inhibitory effect of these compounds on 5-HT receptor.The results showed that compound 4 selectively stimulated 5-HT_(6) receptor.The whole-cell patchclamp experiment showed that 4 reduced excitatory transmitter projection in the prefrontal lobe of rats,and the overall effect was to reduce the downward regulation of subcortical structures in the prefrontal cortex,which has potential value for the development of antidepressant drugs to improve cognitive function.■.

关 键 词：5-HT_(6)R激动剂 10-甲氧基麦角碱 突触电活动 

分 类 号：R914[医药卫生—药物化学]