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Discovery of a Highly Selective and Potent kappa Opioid Receptor Agonist from N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message-Address Concept

文献类型：期刊论文

作者Xiao, Li7; Wang, Yujun8,9; Zhang, Mumei7; Wu, Weiwei2,8,9; Kong, Linghui7; Ma, Yan6,8,9; Xu, Xuejun7,8,9; Liu, Xiao7; He, Qian7; Qian, Yuanyuan7
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-12-26
卷号62期号:24页码:11054-11070
ISSN号0022-2623
DOI10.1021/acs.jmedchem.9b00857
通讯作者Li, Wei(wei-li@fudan.edu.cn) ; Liu, Jinggen(jgliu@mail.shcnc.ac.cn) ; Shao, Liming(limingshao@fudan.edu.cn)
英文摘要Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of N-cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound 4, SLL-039) as a highly selective and potent kappa opioid agonist (kappa, K-i = 0.47 nM, kappa/mu = 682, kappa/delta = 283), which was confirmed by functional assays in vitro and antinociceptive assays in vivo. The in vivo effect could be blocked by pretreatment with the selective kappa antagonist nor-BNI. Moreover, this compound did not induce sedation, a common dose limiting effect of kappa opioid receptor agonists, at its analgesic dose compared to U50,488H. The dissociation of sedation/antinociception found in SLL-039 was assumed to be correlated with the occupation of its benzamide motif in a unique subsite involving V118(2.63), W124(EL1), and E209(EL2).
WOS关键词MORPHINE-THEBAINE GROUP ; NALFURAFINE HYDROCHLORIDE ; MOLECULAR-REARRANGEMENTS ; EFFICACY ; DERIVATIVES ; LIGANDS ; ORVINOLS ; TRK-820 ; ANALOGS ; DELTA
资助项目CAS Key Laboratory of Receptor Research[SIMM1706YKF-02] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040319] ; National Natural Foundation of China[81671322] ; National Natural Foundation of China[81773710] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2017334]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000505633400008
源URL[http://119.78.100.183/handle/2S10ELR8/282331]  
专题中国科学院上海药物研究所
通讯作者Li, Wei; Liu, Jinggen; Shao, Liming
作者单位1.Nanjing Univ Chinese Med, 138 Xianlin Ave, Nanjing 210023, Jiangsu, Peoples R China
2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.Shanghai Inst Technol, 100 Haiquan Rd, Shanghai 201418, Peoples R China
4.Fudan Univ, State Key Lab Med Neurobiol, 138 Yixueyuan Rd, Shanghai 200032, Peoples R China
5.Fudan Univ, Minhang Hosp, 170 Xinsong Rd, Shanghai 201199, Peoples R China
6.Shanghai Univ, Sch Life Sci, 99 Shangda Rd, Shanghai 200444, Peoples R China
7.Fudan Univ, Sch Pharm, Dept Med Chem, 826 Zhangheng Rd, Shanghai 201203, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
9.Collaborat Innovat Ctr Brain Sci, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Xiao, Li,Wang, Yujun,Zhang, Mumei,et al. Discovery of a Highly Selective and Potent kappa Opioid Receptor Agonist from N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message-Address Concept[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(24):11054-11070.
APA Xiao, Li.,Wang, Yujun.,Zhang, Mumei.,Wu, Weiwei.,Kong, Linghui.,...&Shao, Liming.(2019).Discovery of a Highly Selective and Potent kappa Opioid Receptor Agonist from N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message-Address Concept.JOURNAL OF MEDICINAL CHEMISTRY,62(24),11054-11070.
MLA Xiao, Li,et al."Discovery of a Highly Selective and Potent kappa Opioid Receptor Agonist from N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message-Address Concept".JOURNAL OF MEDICINAL CHEMISTRY 62.24(2019):11054-11070.

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来源：上海药物研究所

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