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 | |
Sun, Haifeng1; Zhu, Liyuan2; Yang, Huicui3; Qian, Wangke1; Guo, Lin2; Zhou, Shengbin1; Gao, Bo3; Li, Zeng1; Zhou, Yu1![]() ![]() | |
刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
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2013-02-15 | |
卷号 | 21期号:4页码:856-868 |
关键词 | Asymmetric synthesis Tetrahydroprotoberberines Dopamine receptors Serotonin receptors Multi-action New pharmacological profile |
ISSN号 | 0968-0896 |
DOI | 10.1016/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. |
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关键词 | VENTRAL TEGMENTAL AREA ; PREFRONTAL CORTEX ; RECEPTOR AGONIST ; L-STEPHOLIDINE ; PREPULSE INHIBITION ; PARKINSONS-DISEASE ; STARTLE RESPONSE ; D1 RECEPTORS ; ARYL HALIDES ; NEURONS |
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 |
内容类型 | 期刊论文 |
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. |
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