Allosteric Modulation of Sigma-1 Receptors Elicits Rapid Antidepressant Activity

doi:10.1111/cns.12502

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第二研究室

	Allosteric Modulation of Sigma-1 Receptors Elicits Rapid Antidepressant Activity
	Wang, Yun 1,2; Guo, Lin 1; Jiang, Hua-Feng 1; Zheng, Long-Tai 1; Zhang, Ao3 ; Zhen, Xue-Chu 1
刊名	CNS NEUROSCIENCE & THERAPEUTICS
	2016-05
卷号	22 期号:5 页码:368-377
关键词	Allosteric modulation Antidepressant Brain-derived neurotrophic factor Glycogen synthase kinase 3 Sigma-1 receptors
ISSN号	1755-5930
DOI	10.1111/cns.12502
文献子类	Article
英文摘要	AimsSigma-1 receptors are involved in the pathophysiological process of several neuropsychiatric diseases such as epilepsy, depression. Allosteric modulation represents an important mechanism for receptor functional regulation. In this study, we examined antidepressant activity of the latest identified novel and selective allosteric modulator of sigma-1 receptor 3-methyl-phenyl-2, 3, 4, 5-tetrahydro-1H-benzo[d]azepin-7-ol (SOMCL-668). Methods and ResultsA single administration of SOMCL-668 decreased the immobility time in the forced swimming test (FST) and tailing suspended test in mice, which were abolished by pretreatment of sigma-1 receptor antagonist BD1047. In the chronic unpredicted mild stress (CUMS) model, chronic application of SOMCL-668 rapidly ameliorated anhedonia-like behavior (within a week), accompanying with the enhanced expression of brain-derived neurotrophic factor (BDNF) and phosphorylation of glycogen synthase kinase 3 (GSK3) (Ser-9) in the hippocampus. SOMCL-668 also rapidly promoted the phosphorylation of GSK3 (Ser-9) in an allosteric manner invitro. In the cultured primary neurons, SOMCL-668 enhanced the sigma-1 receptor agonist-induced neurite outgrowth and the secretion of BDNF. ConclusionSOMCL-668, a novel allosteric modulator of sigma-1 receptors, elicits a potent and rapid acting antidepressant effect. The present data provide the first evidence that allosteric modulation of sigma-1 receptors may represent a new approach for antidepressant drug discovery.
资助项目	National Science Foundation of China[81402905] ; National Science Foundation of China[81130023] ; National Science Foundation of China[81373382] ; National Science Foundation of China[81372688] ; National Basic Research Plan (973) of the Ministry of Science and Technology of China[2011CB504403] ; Priority Academic Program Development of Jiangsu Higher Education Institutes (PAPD)[00000000] ; Jiangsu key laboratory grant[BM2013003]
WOS关键词	GLYCOGEN-SYNTHASE KINASE-3 ; MAJOR DEPRESSIVE DISORDER ; NEUROTROPHIC FACTOR ; RAT HIPPOCAMPUS ; KNOCKOUT MICE ; SKF83959 ; BDNF ; MECHANISM ; DISEASE ; INHIBITION
WOS研究方向	Neurosciences & Neurology ; Pharmacology & Pharmacy
语种	英语
出版者	WILEY-BLACKWELL
WOS记录号	WOS:000374377600005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276061]
专题	药理学第二研究室药物化学研究室
通讯作者	Zhen, Xue-Chu
作者单位	1.Soochow Univ, Coll Pharmaceut Sci, Collaborat Innovat Ctr Brain Sci, Jiangsu Key Lab Translat Res Neuropsychiat Dis, 199 Renai Rd, Suzhou, Jiangsu, Peoples R China; 2.Xuzhou Med Coll, Dept Pharmacol, Jiangsu Key Lab New Drug Res & Clin Pharm, Xuzhou, Jiangsu, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Wang, Yun,Guo, Lin,Jiang, Hua-Feng,et al. Allosteric Modulation of Sigma-1 Receptors Elicits Rapid Antidepressant Activity[J]. CNS NEUROSCIENCE & THERAPEUTICS,2016,22(5):368-377.
APA	Wang, Yun,Guo, Lin,Jiang, Hua-Feng,Zheng, Long-Tai,Zhang, Ao,&Zhen, Xue-Chu.(2016).Allosteric Modulation of Sigma-1 Receptors Elicits Rapid Antidepressant Activity.CNS NEUROSCIENCE & THERAPEUTICS,22(5),368-377.
MLA	Wang, Yun,et al."Allosteric Modulation of Sigma-1 Receptors Elicits Rapid Antidepressant Activity".CNS NEUROSCIENCE & THERAPEUTICS 22.5(2016):368-377.