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Discovery, Structure-Activity Relationship, and Mechanistic Studies of 1-((3R,4S)-3-((Dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl)-2-(2,4,5-trifluorophenyl)ethan-1-one as a Novel Potent Analgesic

文献类型：期刊论文

作者Huang, Huoming1; Li, Xueping2,3; Xie, Peng1; Li, Xinwei1; Xu, XueJun2; Qian, Yuanyuan1; Yuan, Congmin1; Meng, Xiangguo4; Chai, JingRui2; Chen, Jing2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-07-08
卷号64期号:13页码:9458-9483
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c00722
通讯作者Li, Wei(wei-li@fudan.edu.cn) ; Wang, YuJun(yjwang@mail.simm.ac.cn) ; Fu, Wei(wfu@fudan.edu.cn)
英文摘要Management of moderate to severe pain relies heavily on opioid analgesics such as morphine, oxycodone, and fentanyl in clinics. However, their prolonged use was associated with undesirable side effects. Many new strategies to reduce side effects have been proposed, but not without disadvantages. Using a hot plate model as a phenotypic screening method, our studies identified (3R,4S)-9d with a new scaffold as a potent analgesic with ED50 values of 0.54 mg/kg and 0.021 mg/kg in hot plate and antiwrithing models, respectively. Mechanistic studies showed that it elicited its analgesic effect via the active metabolite (3R,4S)-10a. The mechanism of (3R,4S)-10a-induced activation of the mu opioid receptor (MOR) was proposed by means of molecular dynamics (MD) simulation.
WOS关键词MU-OPIOID-RECEPTOR ; ACID SUBSTITUTED DERIVATIVES ; MOLECULAR-MECHANISMS ; MORPHINE-TOLERANCE ; MICE LACKING ; TRAMADOL ; AGONIST ; EFFICACY ; INSIGHTS ; LIGAND
资助项目National Natural Science Foundation of China[81773635] ; National Natural Science Foundation of China[82073765] ; Shanghai Science and Technology Development Funds[19431900500] ; Shanghai Science and Technology Development Funds[20S11902400] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2017334]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000672729800036
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/296949]  
专题中国科学院上海药物研究所
通讯作者Li, Wei; Wang, YuJun; Fu, Wei
作者单位1.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Shanghai Univ Med & Hlth Sci, Sch Pharm, Shanghai 201318, Peoples R China
推荐引用方式
GB/T 7714		 Huang, Huoming,Li, Xueping,Xie, Peng,et al. Discovery, Structure-Activity Relationship, and Mechanistic Studies of 1-((3R,4S)-3-((Dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl)-2-(2,4,5-trifluorophenyl)ethan-1-one as a Novel Potent Analgesic[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(13):9458-9483.
APA Huang, Huoming.,Li, Xueping.,Xie, Peng.,Li, Xinwei.,Xu, XueJun.,...&Liu, Jinggen.(2021).Discovery, Structure-Activity Relationship, and Mechanistic Studies of 1-((3R,4S)-3-((Dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl)-2-(2,4,5-trifluorophenyl)ethan-1-one as a Novel Potent Analgesic.JOURNAL OF MEDICINAL CHEMISTRY,64(13),9458-9483.
MLA Huang, Huoming,et al."Discovery, Structure-Activity Relationship, and Mechanistic Studies of 1-((3R,4S)-3-((Dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl)-2-(2,4,5-trifluorophenyl)ethan-1-one as a Novel Potent Analgesic".JOURNAL OF MEDICINAL CHEMISTRY 64.13(2021):9458-9483.

入库方式： OAI收割

来源：上海药物研究所

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