Discovery of Potent and Selective Agonists of delta Opioid Receptor by Revisiting the "Message-Address" Concept

doi:10.1021/acsmedchemlett.5b00423

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

	Discovery of Potent and Selective Agonists of delta Opioid Receptor by Revisiting the "Message-Address" Concept
	Shen, Qing 1; Qian, Yuanyuan 1; Huang, Xiaoqin 2,4; Xu, Xuejun 3; Li, Wei 1; Liu, Jinggen3 ; Fu, Wei 1
刊名	ACS MEDICINAL CHEMISTRY LETTERS
	2016-04
卷号	7 期号:4 页码:391-396
关键词	delta opioid receptor agonist affinity selectivity molecular docking
ISSN号	1948-5875
DOI	10.1021/acsmedchemlett.5b00423
文献子类	Article
英文摘要	The classic "message-address" concept was proposed to address the binding of endogenous peptides to the opioid receptors and was later successfully applied in the discovery of the first nonpeptide 6 opioid receptor (DOR) antagonist naltrindole. By revisiting this concept, and based on the structure of tramadol, we designed a series of novel compounds that act as highly potent and selective agonists of DOR among which (-)-6j showed the highest affinity (K-i = 2.7 nM), best agonistic activity (EC50 = 2.6 nM), and DOR selectivity (more than 1000-fold over the other two subtype opioid receptors). Molecular docking studies suggest that the "message" part of (-)-6j interacts with residue Asp128(3.32) and a neighboring water molecule, and the "address" part of (-)-6j packs with hydrophobic residues Leu300(7.33), Val281(6.55), and Trp284(6.58), rendering DOR selectivity. The discovery of novel compound (-)-6j, and the obtained insights into DOR-agonist binding will help us design more potent and selective DOR agonists.
资助项目	National Natural Science Foundation of China[81473136] ; National Natural Science Foundation of China[81172919] ; Shanghai Science and Technology Development Funds[14431900500]
WOS关键词	NEUROPATHIC PAIN ; ANTAGONISTS ; MODEL
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000374436700011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276088]
专题	药理学第二研究室
通讯作者	Li, Wei; Liu, Jinggen; Fu, Wei
作者单位	1.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China; 2.Rice Univ, Ctr Res Comp, Houston, TX 77005 USA; 3.Chinese Acad Sci, Shanghai Inst Mat Medica, Shanghai 201203, Peoples R China 4.Rice Univ, Ctr Theoret Biol Phys, Houston, TX 77005 USA;
推荐引用方式 GB/T 7714	Shen, Qing,Qian, Yuanyuan,Huang, Xiaoqin,et al. Discovery of Potent and Selective Agonists of delta Opioid Receptor by Revisiting the "Message-Address" Concept[J]. ACS MEDICINAL CHEMISTRY LETTERS,2016,7(4):391-396.
APA	Shen, Qing.,Qian, Yuanyuan.,Huang, Xiaoqin.,Xu, Xuejun.,Li, Wei.,...&Fu, Wei.(2016).Discovery of Potent and Selective Agonists of delta Opioid Receptor by Revisiting the "Message-Address" Concept.ACS MEDICINAL CHEMISTRY LETTERS,7(4),391-396.
MLA	Shen, Qing,et al."Discovery of Potent and Selective Agonists of delta Opioid Receptor by Revisiting the "Message-Address" Concept".ACS MEDICINAL CHEMISTRY LETTERS 7.4(2016):391-396.