Discovery of Potent and Selective Agonists of delta Opioid Receptor by Revisiting the "Message-Address" Concept | |
Shen, Qing1; Qian, Yuanyuan1; Huang, Xiaoqin2,4; Xu, Xuejun3; Li, Wei1; Liu, Jinggen3; Fu, Wei1 | |
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. |
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