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Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D-1, D-2 and serotonin 5-HT1A multi-action profile

文献类型：期刊论文

作者Sun, Haifeng1; Zhu, Liyuan2; Yang, Huicui3; Qian, Wangke1; Guo, Lin2; Zhou, Shengbin1; Gao, Bo3; Li, Zeng1; Zhou, Yu1; Jiang, Hualiang1
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2013-02-15
卷号21期号:4页码:856-868
ISSN号0968-0896
关键词Asymmetric synthesis Tetrahydroprotoberberines Dopamine receptors Serotonin receptors Multi-action New pharmacological profile
DOI10.1016/j.bmc.2012.12.016
文献子类Article
英文摘要An effective and rapid method for the microwave-assisted preparation of the key intermediate for the total synthesis of tetrahydroprotoberberines (THPBs) including l-stepholidine (l-SPD) was developed. Thirty-one THPB derivatives with diverse substituents on A and D ring were synthesized, and their binding affinity to dopamine D-1, D-2 and serotonin 5-HT1A and 5-HT2A receptors were determined. Compounds 18k and 18m were identified as partial agonists at the D-1 receptor with K-i values of 50 and 6.3 nM, while both compounds act as D-2 receptor antagonists (K-i = 305 and 145 nM, respectively) and 5-HT1A receptor full agonists (K-i = 149 and 908 nM, respectively). These two THPBs compounds exerted antipsychotic actions in animal models. Further electrophysiological studies employing single-unit recording in intact animals demonstrated that 18k-excited dopaminergic (DA) neurons are associated with its 5-HT1A receptor agonistic activity. These results suggest that these two compounds targeted to multiple neurotransmitter receptors may present novel lead drugs with new pharmacological profiles for the treatment of schizophrenia. (C) 2012 Elsevier Ltd. All rights reserved.
WOS关键词VENTRAL TEGMENTAL AREA ; PREFRONTAL CORTEX ; RECEPTOR AGONIST ; L-STEPHOLIDINE ; PREPULSE INHIBITION ; PARKINSONS-DISEASE ; STARTLE RESPONSE ; D1 RECEPTORS ; ARYL HALIDES ; NEURONS
资助项目National Basic Research Program of China[2009CB940903] ; National Basic Research Program of China[2009CB52201] ; National Basic Research Program of China[2011CB5C4403] ; National Basic Research Program of China[2012CB518000] ; National Natural Science Foundation of China[21021063] ; National Natural Science Foundation of China[30825042] ; National Natural Science Foundation of China[81130023] ; National Natural Science Foundation of China[81025017] ; National S&T Major Projects[2012ZX09103-101-072] ; The Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions[00000000]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
出版者PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号WOS:000314672900004
源URL[http://119.78.100.183/handle/2S10ELR8/277730]  
专题药理学第二研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
药物化学研究室
通讯作者Zhen, Xuechu
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
2.Chinese Acad Sci, SIMM, Neuropharmacol Lab, Shanghai 201203, Peoples R China;
3.Soochow Univ, Coll Pharmaceut Sci, Dept Pharmacol, Suzhou, Peoples R China
推荐引用方式
GB/T 7714		 Sun, Haifeng,Zhu, Liyuan,Yang, Huicui,et al. Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D-1, D-2 and serotonin 5-HT1A multi-action profile[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2013,21(4):856-868.
APA Sun, Haifeng.,Zhu, Liyuan.,Yang, Huicui.,Qian, Wangke.,Guo, Lin.,...&Liu, Hong.(2013).Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D-1, D-2 and serotonin 5-HT1A multi-action profile.BIOORGANIC & MEDICINAL CHEMISTRY,21(4),856-868.
MLA Sun, Haifeng,et al."Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D-1, D-2 and serotonin 5-HT1A multi-action profile".BIOORGANIC & MEDICINAL CHEMISTRY 21.4(2013):856-868.

入库方式： OAI收割

来源：上海药物研究所

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