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Design, Synthesis, and Structure-Activity Relationship Exploration of Alkyl/Phenylalkyl Piperidine Analogues as Novel Highly Potent and Selective mu Opioid Receptor Agonists

文献类型：期刊论文

作者Huang, Huoming1; Li, Xinwei1; Guo, Wei2; Zhu, Chen1; Qian, Yuanyuan1; Shen, Qing1; Xu, Xuejun3; Li, Wei1; Wang, Yujun3; Fu, Wei1
刊名ACS CHEMICAL NEUROSCIENCE
出版日期2021-01-20
卷号12期号:2页码:285-299
关键词pain opioid analgesic SAR selective MOR agonist molecular dynamics simulations
ISSN号1948-7193
DOI10.1021/acschemneuro.0c00487
通讯作者Wang, Yujun(yjwang@mail.simm.ac.cn) ; Fu, Wei(wfu@fudan.edu.cn)
英文摘要Pain was implicated in many diseases. Despite effectiveness to treat moderate to severe pain, opioid analgesics elicited many side effects, greatly limiting their prescription in clinics. Based on Ml, an active metabolite of tramadol, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)piperidin-4-ol analogues were designed, synthesized, and evaluated in vitro. Among all the compounds tested, compound 23 was found to be a novel, highly selective, and potent MOR agonist (K-i (MOR) = 0.0034 nM, EC50 MOR = 0.68 nM, E-max = 206.5%; K-i (DOR) = 41.67 nM; K KOR = 7.9 nM). Structure-activity relationship exploration showed that the linker between the piperidine ring and the phenyl ring as well as substituent pattern of the phenyl ring played a pivotal role in binding affinity and selectivity. (3R, 4S)-23 (K-i (MOR )= 0.0021 +/- 0.0001 nM, EC50 (MOR) = 0.0013 +/- 0.0001 nM, E-max = 209.1 +/- 1.4%; K DoR = 18.4 +/- 0.7 nM, EC50 (DOR) = 74.5 +/- 2.8 nM, E-max= 267.1 +/- 1.4%; K-i (KOR) = 25.8 +/- 0.2 nM, EC50 (DOR) = 116.2 +/- 4.4 nM, E-max = 209.5 +/- 1.4%) had more potent activity for opioid receptors than its enantiomer (3S, 4R)-23 and was found to be a potent, highly selective MOR agonist with novel scaffold. High binding affinity and selectivity of (3R, 4S)-23 for MOR over KOR and DOR and its mechanism of activating MOR were proposed by docking and molecular dynamics simulations, respectively.
WOS关键词MESSAGE-ADDRESS CONCEPT ; DERIVATIVES ; LIGANDS ; DISCOVERY ; TRAMADOL ; THERAPY ; PAIN
资助项目National Natural Science Foundation of China[81773635] ; Shanghai Science and Technology Development Funds[14431900500] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2017334]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology
语种英语
WOS记录号WOS:000612551800003
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/295741]  
专题中国科学院上海药物研究所
通讯作者Wang, Yujun; Fu, Wei
作者单位1.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China
2.Fudan Univ, Dept Pharmacol, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Huang, Huoming,Li, Xinwei,Guo, Wei,et al. Design, Synthesis, and Structure-Activity Relationship Exploration of Alkyl/Phenylalkyl Piperidine Analogues as Novel Highly Potent and Selective mu Opioid Receptor Agonists[J]. ACS CHEMICAL NEUROSCIENCE,2021,12(2):285-299.
APA Huang, Huoming.,Li, Xinwei.,Guo, Wei.,Zhu, Chen.,Qian, Yuanyuan.,...&Fu, Wei.(2021).Design, Synthesis, and Structure-Activity Relationship Exploration of Alkyl/Phenylalkyl Piperidine Analogues as Novel Highly Potent and Selective mu Opioid Receptor Agonists.ACS CHEMICAL NEUROSCIENCE,12(2),285-299.
MLA Huang, Huoming,et al."Design, Synthesis, and Structure-Activity Relationship Exploration of Alkyl/Phenylalkyl Piperidine Analogues as Novel Highly Potent and Selective mu Opioid Receptor Agonists".ACS CHEMICAL NEUROSCIENCE 12.2(2021):285-299.

入库方式： OAI收割

来源：上海药物研究所

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