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Reversal of subtype-selectivity and function by the introduction of a para-benzamidyl substituent to N-cyclopropylmethyl nornepenthone

文献类型：期刊论文

作者Kong, Linghui1; Ning, Kuan2,3,4; Liu, Xiao1; Lu, Jiashuo5; Chen, Baiyu1; Ye, Rongrong3,4,6; Li, Zixiang1; Jiang, Shuang2,3,4; Tang, Siyuan1; Chai, Jing-Rui3,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-10-05
卷号258页码:15
ISSN号0223-5234
关键词N-cyclopropylmethyl nornepenthone derivatives derivatives Structure-activity relationship MOR antagonist Functional reversal Reversal of subtype-selectivity Opioid use disorder
DOI10.1016/j.ejmech.2023.115589
通讯作者Liu, Jinggen(jgliu@simm.ac.cn) ; Shao, Liming(limingshao@fudan.edu.cn) ; Wang, Yujun(yjwang@simm.ac.cn) ; Li, Wei(wei-li@fudan.edu.cn)
英文摘要The discovery and development of novel & mu;-opioid receptor (MOR) antagonists is a significant area to combat Opioid Use Disorder (OUD). In this work, a series of para-substituted N-cyclopropylmethyl-nornepenthone derivatives were designed and synthesized and pharmacologically assayed. Compound 6a was identified as a selective MOR antagonist both in vitro and in vivo. Its molecular basis was elucidated using molecular docking and MD simulations. A subpocket on the extracellular side of the TM2 domain of MOR, in particular the residue Y2.64, was proposed to be responsible for the reversal of subtype selectivity and functional reversal of this compound.
WOS关键词KAPPA-OPIOID RECEPTOR ; BETA-FUNALTREXAMINE ; MU ; POTENT ; ANTAGONIST ; DESIGN ; AGONIST ; CLOCINNAMOX ; DISCOVERY ; MORPHINE
资助项目Major Project of the Science and Technology Innovation 2030 of China[2021ZD0202900] ; Major Project of the Science and Technology Innovation 2030 of China[2021ZD0203500] ; National Natural Science Foundation of China[82030112] ; National Natural Science Foundation of China[81773710] ; National Natural Science Foundation of China[82273853] ; National Natural Science Foundation of China[82073765] ; Science and Technology Commission of Shanghai Municipality[20ZR1468200] ; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions[NYKFKT2019015]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:001031810300001
源URL[http://119.78.100.183/handle/2S10ELR8/306764]  
专题新药研究国家重点实验室
通讯作者Liu, Jinggen; Shao, Liming; Wang, Yujun; Li, Wei
作者单位1.Fudan Univ, Sch Pharm, Dept Med Chem, 826 Zhangheng Rd, Shanghai 201203, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
5.Dalian Med Univ, Dept Pharm, Dalian 116044, Peoples R China
6.Shanghai Inst Technol, Sch Chem & Environm Engn, Shanghai 201418, Peoples R China
7.Fudan Univ, State Key Lab Med Neurobiol, 138 Yixueyuan Rd, Shanghai 200032, Peoples R China
8.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Kong, Linghui,Ning, Kuan,Liu, Xiao,et al. Reversal of subtype-selectivity and function by the introduction of a para-benzamidyl substituent to N-cyclopropylmethyl nornepenthone[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,258:15.
APA Kong, Linghui.,Ning, Kuan.,Liu, Xiao.,Lu, Jiashuo.,Chen, Baiyu.,...&Li, Wei.(2023).Reversal of subtype-selectivity and function by the introduction of a para-benzamidyl substituent to N-cyclopropylmethyl nornepenthone.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,258,15.
MLA Kong, Linghui,et al."Reversal of subtype-selectivity and function by the introduction of a para-benzamidyl substituent to N-cyclopropylmethyl nornepenthone".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 258(2023):15.

入库方式： OAI收割

来源：上海药物研究所

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