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Structure-Activity Relationship of N-Cyclopropylmethyl-7α-[para-(arylcarboxamido)phenyl]-6,14-endoethano-tetrahydronorthebaines as Potent and Selective Kappa Opioid Receptor Agonists

文献类型：期刊论文

作者Kong, Linghui6; Yao, Songyu4,5; Zhang, Denggao6; Gui, Jiangwen2,3; Chen, Baiyu6; Liu, Min2; Tang, Siyuan6; Hu, Chuyuan2,4; Duan, Shaoliang6; Wang, Biying2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-08-14
卷号68期号:15页码:15889-15909
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c00882
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Research on KOR agonists with reduced central nervous system side effects represents a significant area in analgesic studies. Herein, a structure-activity relationship analysis was performed for a series of N-cyclopropylmethyl-7 alpha-[para-(arylcarboxamido)phenyl]-6,14-endoethano-tetrahydronorthebaines. Several highly selective and potent KOR agonists have been identified. Notably, compound 5i exhibited a subpicomolar binding affinity for KOR and exceptional subtype selectivity over MOR and DOR, consistent with its in vitro functional activities. It was identified as a G protein-biased KOR agonist, and its molecular interactions with KOR were elucidated. Additionally, this compound exhibited potent, dose-dependent, long-lasting, and KOR-mediated antinociceptive activity in both hot plate and abdominal constriction assays. It did not display any noticeable aversion or sedation in rodent models. These pharmacological characteristics suggest that compound 5i is a promising candidate for further studies.
WOS关键词2.5 MU-G ; POSTMARKETING SURVEILLANCE ; MOLECULAR-REARRANGEMENTS ; NALFURAFINE ; DISCOVERY ; EFFICACY ; SAFETY ; PAIN ; DERIVATIVES ; ANALGESICS
资助项目Natural Science Foundation of Shanghai Municipality[2021ZD0203500] ; Natural Science Foundation of Shanghai Municipality[2021ZD0202900] ; Major Project of the Science and Technology Innovation 2030 of China[82030112] ; Major Project of the Science and Technology Innovation 2030 of China[82273853] ; Major Project of the Science and Technology Innovation 2030 of China[82073765] ; National Natural Science Foundation of China[24ZR1413700] ; National Natural Science Foundation of China[23ZR1474900] ; Natural Science Foundation of Shanghai[2024CXPT029] ; Key R&D Program of Shandong Province, China[2024JCYJ045] ; Fundamental Research Projects of Science & Technology Innovation and development Plan in Yantai City ; Taishan Scholars Program[SYS202205] ; Shandong Laboratory Program
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001539133900001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/321138]  
专题中国科学院上海药物研究所
通讯作者Liu, Jinggen; Shao, Liming; Wang, Yujun; Li, Wei
作者单位1.Zhejiang Chinese Med Univ, Sch Pharmaceut Sci, Hangzhou 310053, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
3.Anhui Univ Chinese Med, Sch Pharm, Hefei 230012, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
6.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Kong, Linghui,Yao, Songyu,Zhang, Denggao,et al. Structure-Activity Relationship of N-Cyclopropylmethyl-7α-[para-(arylcarboxamido)phenyl]-6,14-endoethano-tetrahydronorthebaines as Potent and Selective Kappa Opioid Receptor Agonists[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(15):15889-15909.
APA Kong, Linghui.,Yao, Songyu.,Zhang, Denggao.,Gui, Jiangwen.,Chen, Baiyu.,...&Li, Wei.(2025).Structure-Activity Relationship of N-Cyclopropylmethyl-7α-[para-(arylcarboxamido)phenyl]-6,14-endoethano-tetrahydronorthebaines as Potent and Selective Kappa Opioid Receptor Agonists.JOURNAL OF MEDICINAL CHEMISTRY,68(15),15889-15909.
MLA Kong, Linghui,et al."Structure-Activity Relationship of N-Cyclopropylmethyl-7α-[para-(arylcarboxamido)phenyl]-6,14-endoethano-tetrahydronorthebaines as Potent and Selective Kappa Opioid Receptor Agonists".JOURNAL OF MEDICINAL CHEMISTRY 68.15(2025):15889-15909.

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来源：上海药物研究所

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