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

doi:10.1021/acs.jmedchem.1c00722

	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
	Huang, Huoming 1; Li, Xueping 2,3; Xie, Peng 1; Li, Xinwei 1; Xu, XueJun 2; Qian, Yuanyuan 1; Yuan, Congmin 1; Meng, Xiangguo 4; Chai, JingRui 2; Chen, Jing 2
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-07-08
卷号	64 期号:13 页码:9458-9483
ISSN号	0022-2623
DOI	10.1021/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.
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关键词	MU-OPIOID-RECEPTOR ; ACID SUBSTITUTED DERIVATIVES ; MOLECULAR-MECHANISMS ; MORPHINE-TOLERANCE ; MICE LACKING ; TRAMADOL ; AGONIST ; EFFICACY ; INSIGHTS ; LIGAND
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000672729800036
内容类型	期刊论文
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.