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

doi:10.1016/j.bmc.2012.12.016

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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
	Sun, Haifeng 1; Zhu, Liyuan 2; Yang, Huicui 3; Qian, Wangke 1; Guo, Lin 2; Zhou, Shengbin 1; Gao, Bo 3; Li, Zeng 1; Zhou, Yu1 ; Jiang, Hualiang1
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	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.