Allosteric modulation of sigma-1 receptors elicits anti-seizure activities

doi:10.1111/bph.13195

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 anti-seizure activities
	Guo, Lin 1,4; Chen, Yanke 1,4; Zhao, Rui 1,4; Wang, Guanghui 1,4; Friedman, Eitan 2; Zhang, Ao3 ; Zhen, Xuechu 1,4
刊名	BRITISH JOURNAL OF PHARMACOLOGY
	2015-08
卷号	172 期号:16 页码:4052-4065
ISSN号	0007-1188
DOI	10.1111/bph.13195
文献子类	Article
英文摘要	Background and PurposeApplication of orthosteric sigma-1 receptor agonists as anti-seizure drugs has been hindered by questionable efficacy and potential adverse effects. Here, we have investigated the anti-seizure effects of the novel and potent allosteric modulator of sigma-1 receptors, SKF83959 and its derivative SOMCL-668 (3-methyl-phenyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol). Experimental ApproachThe anti-seizure effects of SKF83959 were investigated in three mouse models, maximal electroshock seizures, pentylenetetrazole-induced convulsions and kainic acid-induced status epilepticus'. Also, in rats, the cortical epileptiform activity induced by topical application of picrotoxin was recorded in electrocorticograms. In rat hippocampal brain slices, effects of the drugs on the high potassium-evoked epileptiform local field potentials were studied. Anti-seizure activities of SOMCL-668, a newly developed sigma-1 receptor selective allosteric modulator, were also investigated. Key ResultsSKF83959 (20, 40mgkg(-1)) exhibited anti -seizure actitity in the three mouse models and reduced the cortical epileptiform activity without alteration of spontaneous motor activity and motor coordination. These effects were blocked by the sigma-1 receptor antagonist BD1047, but not the dopamine D-1 receptor antagonist SCH23390. SKF83959 alone did not directly inhibit the epileptiform firing of CA3 neurons induced by high potassium in hippocampal slices, but did potentiate inhibition by the orthosteric sigma-1 receptor agonist SKF10047. Lastly, a selective sigma-1 receptor allosteric modulator SOMCL-668, which does not bind to dopamine receptors, exerted similar anti-seizure activities. Conclusions and ImplicationsSKF83959 and SOMCL-668 displayed anti-seizure activities, indicating that allosteric modulation of sigma-1 receptors may provide a novel approach for discovering new anti-seizure drugs.
资助项目	National Science Foundation of China[81402905] ; National Science Foundation of China[81130023] ; National Science Foundation of China[30825042] ; National Basic Research Plan (973) of the Ministry of Science and Technology of China[2011CB504403] ; Priority Academic Program Development of Jiangsu Higher Education Institute (PAPD)[00000000] ; Jiangsu Key Laboratory[BM2013003]
WOS关键词	PROTEIN-COUPLED RECEPTORS ; ANTIEPILEPTIC DRUGS ; ARRIVE GUIDELINES ; DOPAMINE-RECEPTOR ; CONCISE GUIDE ; GUINEA-PIG ; SKF83959 ; PHARMACOLOGY ; RAT ; MICE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	WILEY-BLACKWELL
WOS记录号	WOS:000358454100009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276457]
专题	药理学第二研究室药物化学研究室
通讯作者	Zhen, Xuechu
作者单位	1.Soochow Univ, Coll Pharmaceut Sci, Dept Pharmacol, Suzhou 215123, Jiangsu, Peoples R China; 2.CUNY, Dept Pharmacol & Neurosci, Sch Med CCNY, New York, NY 10021 USA; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 200031, Peoples R China 4.Soochow Univ, Coll Pharmaceut Sci, Jiangsu Key Lab Translat Res & Therapy Neuropsych, Suzhou 215123, Jiangsu, Peoples R China;
推荐引用方式 GB/T 7714	Guo, Lin,Chen, Yanke,Zhao, Rui,et al. Allosteric modulation of sigma-1 receptors elicits anti-seizure activities[J]. BRITISH JOURNAL OF PHARMACOLOGY,2015,172(16):4052-4065.
APA	Guo, Lin.,Chen, Yanke.,Zhao, Rui.,Wang, Guanghui.,Friedman, Eitan.,...&Zhen, Xuechu.(2015).Allosteric modulation of sigma-1 receptors elicits anti-seizure activities.BRITISH JOURNAL OF PHARMACOLOGY,172(16),4052-4065.
MLA	Guo, Lin,et al."Allosteric modulation of sigma-1 receptors elicits anti-seizure activities".BRITISH JOURNAL OF PHARMACOLOGY 172.16(2015):4052-4065.