The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent kappa-Opioid Agonistic Activities

doi:10.1021/acschemneuro.6b00321

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

	The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent kappa-Opioid Agonistic Activities
	Li, Wei 2; Long, Jian-Dong 1; Qian, Yuan-Yuan 2; Long, Yu 3; Xu, Xue-Jun 1; Wang, Yu-Jun1 ; Shen, Qing 2; Wang, Zuo-Neng 2; Yang, Xi-Cheng 2; Xiao, Li 2
刊名	ACS CHEMICAL NEUROSCIENCE
	2017-04
卷号	8 期号:4 页码:766-776
关键词	kappa-opioid receptor mu-opioid receptor nepenthones 4,5-epoxymorphinans pharmacological heterogeneity structure activity relationship binding structure
ISSN号	1948-7193
DOI	10.1021/acschemneuro.6b00321
文献子类	Article
英文摘要	To develop novel analgesics with no side effects or less side effects than traditional opioids is highly demanded to treat opioid receptor mediated,pain and addiction issues. Recently, K-opioid receptor (KOR) has been established as an attractive target, although its selective agonists could bear heterogeneous pharmacological activities. In this study, we designed and synthesized two new series of nepenthone derivatives by inserting a spacer (carbonyl) between 6 alpha,14 alpha-endo-ethenylthebaine and the 7 alpha-phenyl substitution of the skeleton and by substituting the 17-N-methyl group with a cyclopropylmethyl group. We performed in vitro tests (binding and functional assays) and molecular docking operations on our newly designed compounds. The results of wet-experimental measures and modeled binding structures demonstrate that these new compounds are selective KOR agonists with nanomolar level affinities. Compound 4 from these new derivatives showed the highest affinity (K-i = 0.4 +/- 0.1 nM) and the highest selectivity (mu/kappa = 339, delta/kappa = 2034) toward KOR The in vivo tests revealed that compound 4 is able to induce stronger (ED50 = 2.1 mg/kg) and much longer antinociceptive effect than that of the typical KOR agonist U50488H (ED50 = 4.4 mg/kg). Therefore, compound 4 can be used as a perfect lead compound for future design of potent analgesics acting through KOR
资助项目	Natural Science Foundation of Shanghai[08ZR1401500] ; Shanghai Science and Technology Development Funds[14431900500] ; National Natural Science Foundation of China[81473136] ; National Natural Science Foundation of China[81130087] ; National Natural Science Foundation of China[91232716] ; State Key Laboratory of Toxicology and Medical Countermeasures (Academy of Military Medical Science)[TMC201501] ; Ministry of Science and Technology of China[2013CB835100] ; Ministry of Science and Technology of China[2015CBSS3500]
WOS关键词	RECEPTOR AGONIST ; NALFURAFINE HYDROCHLORIDE ; HEMODIALYSIS-PATIENTS ; ANALGESIC EFFICACY ; MORPHINE ; ANTAGONIST ; PAIN ; REARRANGEMENTS ; DERIVATIVES ; ACTIVATION
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000399968400012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272716]
专题	药理学第二研究室
通讯作者	Liu, Jing-Gen; Fu, Wei
作者单位	1.Chinese Acad Sci & Collaborat Innovat Ctr Brain S, Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China; 3.Dalian Med Univ, Dept Pharm, Dalian 116044, Peoples R China
推荐引用方式 GB/T 7714	Li, Wei,Long, Jian-Dong,Qian, Yuan-Yuan,et al. The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent kappa-Opioid Agonistic Activities[J]. ACS CHEMICAL NEUROSCIENCE,2017,8(4):766-776.
APA	Li, Wei.,Long, Jian-Dong.,Qian, Yuan-Yuan.,Long, Yu.,Xu, Xue-Jun.,...&Fu, Wei.(2017).The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent kappa-Opioid Agonistic Activities.ACS CHEMICAL NEUROSCIENCE,8(4),766-776.
MLA	Li, Wei,et al."The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent kappa-Opioid Agonistic Activities".ACS CHEMICAL NEUROSCIENCE 8.4(2017):766-776.