Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: Selective inhibitors of dopamine D-1 receptor

doi:10.1016/j.bmc.2012.05.057

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	Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: Selective inhibitors of dopamine D-1 receptor
	Qian, Wangke 1,3; Lu, Weijian 3; Sun, Haifeng 3; Li, Zeng 3; Zhu, Liyuan 3; Zhao, Rui 2; Zhang, Lei 3; Zhou, Shengbin 3; Zhou, Yu3 ; Jiang, Hualiang3
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	2012-08-01
卷号	20 期号:15 页码:4862-4871
关键词	Tetrahydroprotoberberine Dopamine receptor Anti-substance abuse Antagonist
ISSN号	0968-0896
DOI	10.1016/j.bmc.2012.05.057
文献子类	Article
英文摘要	A series of new tetrahydroprotoberberine (THPB) derivatives were designed, synthesized, and tested for their binding affinity towards dopamine (D-1 and D-2) and serotonin (5-HT1A and 5-HT2A) receptors. Many of the THPB compounds exhibited high binding affinity and activity at the dopamine D-1 receptor, as well as high selectivity for the D-1 receptor over the D-2, 5-HT1A, and 5-HT2A receptors. Among these, compound 19c exhibited a promising D-1 receptor binding affinity (K-i = 2.53 nM) and remarkable selectivity versus D2R (inhibition = 81.87%), 5-HT1AR (inhibition = 61.70%), and 5-HT2AR (inhibition = 24.96%). Compared with l-(S)-stepholidine (l-SPD) (D-1 K-i = 6.23 nM, D-2 K-i = 56.17 nM), compound 19c showed better binding affinity for the D-1 receptor (2.5-fold higher) and excellent D-2/D-1 selectivity. Functional assays found compounds 18j, 18k, and 19c are pure D-1 receptor antagonists. These results indicate that removing the C10 hydroxy group and introducing a methoxy group at C11 of the pharmacophore of l-SPD can reverse the function of THPB compounds at the D-1 receptor. These results are in accord with molecular docking studies. Crown Copyright (C) 2012 Published by Elsevier Ltd. All rights reserved.
资助项目	National Basic Research Program of China[2009CB940903] ; National Basic Research Program of China[2009CB522000] ; National Basic Research Program of China[2011CB5C4403] ; National Basic Research Program of China[2012CB518000] ; National Natural Science Foundation of China[20721003] ; 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] ; Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions[00000000]
WOS关键词	INDUCED REINSTATEMENT ; PARKINSONS-DISEASE ; ANTIPSYCHOTIC DRUG ; L-STEPHOLIDINE ; D1 ANTAGONIST ; (-)-STEPHOLIDINE ; ANALOGS ; POTENT ; LIGANDS ; AGONIST
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:000306480200030
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278003]
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.Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Shenyang 110016, Liaoning, Peoples R China; 2.Soochow Univ, Coll Pharmaceut Sci, Dept Pharmacol, Suzhou 215123, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Qian, Wangke,Lu, Weijian,Sun, Haifeng,et al. Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: Selective inhibitors of dopamine D-1 receptor[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2012,20(15):4862-4871.
APA	Qian, Wangke.,Lu, Weijian.,Sun, Haifeng.,Li, Zeng.,Zhu, Liyuan.,...&Liu, Hong.(2012).Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: Selective inhibitors of dopamine D-1 receptor.BIOORGANIC & MEDICINAL CHEMISTRY,20(15),4862-4871.
MLA	Qian, Wangke,et al."Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: Selective inhibitors of dopamine D-1 receptor".BIOORGANIC & MEDICINAL CHEMISTRY 20.15(2012):4862-4871.