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Discovery of an M-Substituted N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active kappa-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile

文献类型：期刊论文

作者He, Qian1; Wei, Yuanyuan2,3,4; Liu, Xiao1; Ye, Rongrong5; Kong, Linghui1; Li, Zixiang1; Jiang, Shuang6; Yu, Linqian1; Chai, Jingrui2,3; Xie, Qiong1
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-08-26
卷号64期号:16页码:12414-12433
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c01082
通讯作者Wang, Yujun(yjwang@mail.simm.ac.cn) ; Li, Wei(wei-li@fudan.edu.cn) ; Liu, Jinggen(jgliu@simm.ac.cn) ; Shao, Liming(limingshao@fudan.edu.cn)
英文摘要The search for selective kappa opioid receptor (kappa OR) agonists with an improved safety profile is an area of interest in opioid research. In this work, a series of m-substituted analogs were designed, synthesized, and assayed, resulting in the identification of compound 6c (SLL-1206) as a kappa OR agonist with single-digit nanomolar activities. The subtype selectivity of compound 6c appeared to be a consequence of an enormous decrease in the affinity for mu OR and delta OR, rather than a significant increase in the affinity for kappa OR, which was not the case for SLL-039, another selective and potent kappa OR agonist identified in our previous work. Besides reduced central nervous system effects, SLL-1206 exhibited substantially improved physicochemical and pharmacokinetic properties compared with SLL-039, with increases of over 20-fold in aqueous solubility and approximately 40-fold in oral bioavailability in rats.
WOS关键词MORPHINE-THEBAINE GROUP ; MOLECULAR-REARRANGEMENTS ; EFFICACY ; ANALOGS ; NALFURAFINE ; ORVINOLS ; PAIN ; ANTINOCICEPTION ; DERIVATIVES ; ANALGESICS
资助项目Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040319] ; National Natural Science Foundation of China[81671322] ; National Natural Science Foundation of China[82030112] ; National Natural Science 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
WOS记录号WOS:000692012400035
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/297839]  
专题中国科学院上海药物研究所
通讯作者Wang, Yujun; Li, Wei; Liu, Jinggen; Shao, Liming
作者单位1.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
3.Collaborat Innovat Ctr Brain Sci, Shanghai 201203, Peoples R China
4.China Pharmaceut Univ, Sch Basic Med Sci & Clin Pharm, Nanjing 210009, Jiangsu, Peoples R China
5.Shanghai Inst Technol, Sch Chem & Environm Engn, Shanghai 201418, Peoples R China
6.Nanjing Univ Chinese Med, Sch Pharm, Nanjing 210023, Peoples R China
7.Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China
推荐引用方式
GB/T 7714		 He, Qian,Wei, Yuanyuan,Liu, Xiao,et al. Discovery of an M-Substituted N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active kappa-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(16):12414-12433.
APA He, Qian.,Wei, Yuanyuan.,Liu, Xiao.,Ye, Rongrong.,Kong, Linghui.,...&Shao, Liming.(2021).Discovery of an M-Substituted N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active kappa-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile.JOURNAL OF MEDICINAL CHEMISTRY,64(16),12414-12433.
MLA He, Qian,et al."Discovery of an M-Substituted N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active kappa-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile".JOURNAL OF MEDICINAL CHEMISTRY 64.16(2021):12414-12433.

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来源：上海药物研究所

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