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Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect

文献类型：期刊论文

作者Li, Zixiang7; Ye, Rufeng4,5,6; He, Qian7; Lu, Jiashuo3,5,6; Sun, Yanting2; Sun, Xiujian2; Tang, Siyuan7; Hu, Shuyang5,6; Chai, Jingrui5,6; Kong, Linghui7
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-04-22
卷号67期号:9页码:7112-7129
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c02439
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 into kappa opioid receptor (KOR) agonists with attenuated central-nervous-system side effects is a critical focus for developing productive and safe analgesics. Herein, a series of ortho-substituted N-cyclopropylmethyl-7 alpha-phenyl-6,14-endoethano-tetrahydronorthebaines were designed, synthesized, and subjected to bioassays. Compound 7a exhibited high subtype selectivity and potent agonistic activity toward KOR (KOR, K-i = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; [S-35]GTP gamma S binding, EC50 = 3.4 nM). Additionally, this compound exhibited robust and persistent antinociceptive effects in rodent models with different animal strains (hot plate test, ED50 = 0.20-0.30 mg/kg, i.p.; abdominal constriction test, ED50 = 0.20-0.60 mg/kg, i.p.), with its KOR-mediated mechanism for antinociception firmly established. Notably, compound 7a, unlike conventional KOR agonists, displayed minimal sedation and aversion at the antinociceptive ED50 dose. This feature addresses a crucial limitation in existing KOR agonists, positioning compound 7a as a promising novel therapeutic agent.
WOS关键词2.5 MU-G ; POSTMARKETING SURVEILLANCE ; PHARMACOLOGICAL-PROPERTIES ; NALFURAFINE HYDROCHLORIDE ; HEMODIALYSIS-PATIENTS ; SUBTYPE-SELECTIVITY ; SALVINORIN-A ; EFFICACY ; TRK-820 ; DELTA
资助项目National Natural Science Foundation of China[2021ZD0203500] ; National Natural Science Foundation of China[2021ZD0202900] ; Major Project of the Science and Technology Innovation 2030 of China[82030112] ; Major Project of the Science and Technology Innovation 2030 of China[81773710] ; 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[20ZR1468200] ; Science and Technology Commission of Shanghai Municipality[NYKFKT2019015] ; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001227829400001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/311249]  
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.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
2.Zhejiang Chinese Med Univ, Clin Med Coll 3, Dept Neurobiol & Acupuncture Res, Key Lab Acupuncture & Neurobiol Zhejiang Prov, Hangzhou 310053, Peoples R China
3.Dalian Med Univ, Dept Pharm, Dalian 116044, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
7.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Li, Zixiang,Ye, Rufeng,He, Qian,et al. Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(9):7112-7129.
APA Li, Zixiang.,Ye, Rufeng.,He, Qian.,Lu, Jiashuo.,Sun, Yanting.,...&Li, Wei.(2024).Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect.JOURNAL OF MEDICINAL CHEMISTRY,67(9),7112-7129.
MLA Li, Zixiang,et al."Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect".JOURNAL OF MEDICINAL CHEMISTRY 67.9(2024):7112-7129.

入库方式： OAI收割

来源：上海药物研究所

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