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Discovery, stereospecific characterization and peripheral modification of 1-(pyrrolidin-1-ylmethyl)-2-[(6-chloro-3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinolines as novel selective kappa opioid receptor agonists

文献类型：期刊论文

作者Gan, Zong-Jie6; Wang, Yu-Hua1,3; Xu, Yun-Gen5,6; Guo, Ting6; Wang, Jun5; Song, Qiao6; Xu, Xue-Jun3; Hu, Shi-Yuan5; Wang, Yu-Jun3; Wang, De-Chuan5
刊名ORGANIC & BIOMOLECULAR CHEMISTRY
出版日期2015
卷号13期号:20页码:5656-5673
ISSN号1477-0520
DOI10.1039/c5ob00350d
文献子类Article
英文摘要A novel series of 1-(pyrrolidin-1-ylmethyl)-2-[(3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinoline derivatives maj-3a-maj-3u were synthesized and evaluated in vitro for their binding affinity at kappa-opioid receptors. Maj-3c displayed the highest affinity for kappa-opioid receptors (K-i = 0.033 nM) among all the compounds evaluated. Furthermore, all four stereoisomers of compound 3c were prepared, and (1S,18S)-3c was identified as the most potent (K-i = 0.0059 nM) kappa-opioid receptor agonist among the four stereoisomers. Maj-3c produced significant antinociception (ED50 = 0.000406 mg kg(-1)) compared to U-50,488H and original BRL 52580 in the acetic acid writhing assay, but its strong sedative effect (ED50 = 0.000568 mg kg(-1)) observed in the mouse rotation test reduced its druggability. To minimize the central nervous system side effects, a series of hydroxyl-containing analogs of maj-3c were synthesized, and maj-11a was found to be a potent.-opioid receptor agonist (K-i = 35.13 nM). More importantly, the dose for the sedative effect (ED50 = 9.29 mg kg(-1)) of maj-11a was significantly higher than its analgesic dose (ED50 = 0.392 mg kg(-1)), which made it a promising peripheral analgesic candidate compound with weak sedative side effects.
WOS关键词ANALGESIC AGENTS ; DERIVATIVES ; ACIDS
资助项目Foundation of National Natural Science of China[81072520] ; Foundation of National Natural Science of China[81130087] ; Foundation of National Natural Science of China[91232716] ; Ministry of Science and Technology of China[2009ZX09103-096] ; Ministry of Science and Technology of China[2009CB522005] ; Ministry of Science and Technology of China[2013CB835100] ; Ministry of Science and Technology of China[2012ZX09301001-005] ; Ministry of Science and Technology of China[2012BAI01B00] ; Jiangsu Province Science and Technology Support Program (Social Development) project[BE2009676]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:000354438400015
出版者ROYAL SOC CHEMISTRY
源URL[http://119.78.100.183/handle/2S10ELR8/276731]  
专题药理学第二研究室
通讯作者Xu, Yun-Gen
作者单位1.Nanjing Univ Chinese Med, Sch Pharm, Nanjing 210046, Jiangsu, Peoples R China;
2.Yangze River Pharmaceut Grp, Taizhou 225321, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
4.China Pharmaceut Univ, Dept Pharmaceut Anal, Nanjing 210009, Jiangsu, Peoples R China;
5.China Pharmaceut Univ, Dept Med Chem, Nanjing 210009, Jiangsu, Peoples R China;
6.China Pharmaceut Univ, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 210009, Jiangsu, Peoples R China;
推荐引用方式
GB/T 7714		 Gan, Zong-Jie,Wang, Yu-Hua,Xu, Yun-Gen,et al. Discovery, stereospecific characterization and peripheral modification of 1-(pyrrolidin-1-ylmethyl)-2-[(6-chloro-3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinolines as novel selective kappa opioid receptor agonists[J]. ORGANIC & BIOMOLECULAR CHEMISTRY,2015,13(20):5656-5673.
APA Gan, Zong-Jie.,Wang, Yu-Hua.,Xu, Yun-Gen.,Guo, Ting.,Wang, Jun.,...&Liu, Jing-Gen.(2015).Discovery, stereospecific characterization and peripheral modification of 1-(pyrrolidin-1-ylmethyl)-2-[(6-chloro-3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinolines as novel selective kappa opioid receptor agonists.ORGANIC & BIOMOLECULAR CHEMISTRY,13(20),5656-5673.
MLA Gan, Zong-Jie,et al."Discovery, stereospecific characterization and peripheral modification of 1-(pyrrolidin-1-ylmethyl)-2-[(6-chloro-3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinolines as novel selective kappa opioid receptor agonists".ORGANIC & BIOMOLECULAR CHEMISTRY 13.20(2015):5656-5673.

入库方式： OAI收割

来源：上海药物研究所

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