The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent kappa-Opioid Agonistic Activities
文献类型：期刊论文
| 作者 | Li, Wei2; Long, Jian-Dong1; Qian, Yuan-Yuan2; Long, Yu3; Xu, Xue-Jun1; Wang, Yu-Jun1 ; Shen, Qing2; Wang, Zuo-Neng2; Yang, Xi-Cheng2; Xiao, Li2
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| 刊名 | ACS CHEMICAL NEUROSCIENCE
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| 出版日期 | 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 |
| WOS关键词 | RECEPTOR AGONIST ; NALFURAFINE HYDROCHLORIDE ; HEMODIALYSIS-PATIENTS ; ANALGESIC EFFICACY ; MORPHINE ; ANTAGONIST ; PAIN ; REARRANGEMENTS ; DERIVATIVES ; ACTIVATION |
| 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研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology |
| 语种 | 英语 |
| WOS记录号 | WOS:000399968400012 |
| 出版者 | AMER CHEMICAL SOC |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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