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Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based kappa Opioid Receptor (kappa OR) Agonists Using the Strategy of Bridging

文献类型：期刊论文

作者Liu, Xiao3; Jiang, Shuang2,4,5; Kong, Linghui3; Ye, Rongrong2,5,6; Xiao, Li3; Xu, Xuejun2,5; He, Qian3; Wei, Yuanyuan7; Li, Zixiang3; Sun, Huijiao3
刊名ACS CHEMICAL NEUROSCIENCE
出版日期2021-03-17
卷号12期号:6页码:1018-1030
ISSN号1948-7193
关键词Morphinans arylacetamidyl substituent kappa opioid receptor modulators structure-activity relationships
DOI10.1021/acschemneuro.1c00034
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kappa opioid receptor (kappa OR) is a subtype of opioid receptors, and there are two major kappa OR agonists currently available, morphinans and arylacetamides, which are structurally distinct from each other. Numerous efforts had been made to correlate these series of compounds in order to establish a consensus binding pattern for kappa OR agonists. Unfortunately, no morphinan-based agent with an arylacetamidyl substituent has been identified as a kappa OR agonist with a pharmacological profile similar to arylacetamides. Since the recently described morphinan-based compound SLL-039 was identified as a selective and potent kappa OR agonist that contains a unique benzamidyl substituent in structure similar to arylacetamides, numerous arylacetamidyl substituents were introduced to this scaffold to examine whether the structure-activity relationships (SARs) of arylacetamides in conferring kappa OR agonistic activities could be reproduced by these analogues. Thus, a series of Ncyclopropylmethyl-7-alpha-arylacetamidylphenyl-6,14-endoethanotetrahydronorthebaine analogues were designed, synthesized, and assayed for biological activities. Among these compounds, compound 4j with a 3',4'-dimethylphenylacetamidyl substituent showed a single digit low nanomolar affinity to the kappa OR and relatively high subtype selectivity in binding assays, but this profile was not reproduced in functional assays. In contrast, compound 4i displayed moderately selective kappa OR agonistic activities in functional assays, which was inconsistent with its nonselective nature in binding assays. Overall, introduction of an arylacetamidyl substituent to the morphinan-based scaffold was associated with pharmacological diversity in both binding and functional activities on opioid receptors in vitro. The resultant SARs were inconsistent with that of classical arylacetamides as kappa OR agonists, despite bearing a similar arylacetamidyl substituent in the structure. Therefore, the arylacetamidyl substituent of the morphinan-based scaffold was found to be disconnected from that of arylacetamides in conferring kappa OR activities.
资助项目Strategic Priority Research Program of the Chinese Academy of Sciences[XDA 12040319] ; National Natural Foundation of China[81773710] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2017334]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000630313500008
源URL[http://119.78.100.183/handle/2S10ELR8/295492]  
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, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China
2.Collaborat Innovat Ctr Brain Sci, Shanghai 201203, Peoples R China
3.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
6.Shanghai Inst Technol, Sch Chem & Environm Engn, Shanghai 201418, Peoples R China
7.China Pharmaceut Univ, Sch Basic Med Sci & Clin Pharm, Nanjing 210009, Peoples R China
8.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Xiao,Jiang, Shuang,Kong, Linghui,et al. Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based kappa Opioid Receptor (kappa OR) Agonists Using the Strategy of Bridging[J]. ACS CHEMICAL NEUROSCIENCE,2021,12(6):1018-1030.
APA Liu, Xiao.,Jiang, Shuang.,Kong, Linghui.,Ye, Rongrong.,Xiao, Li.,...&Shao, Liming.(2021).Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based kappa Opioid Receptor (kappa OR) Agonists Using the Strategy of Bridging.ACS CHEMICAL NEUROSCIENCE,12(6),1018-1030.
MLA Liu, Xiao,et al."Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based kappa Opioid Receptor (kappa OR) Agonists Using the Strategy of Bridging".ACS CHEMICAL NEUROSCIENCE 12.6(2021):1018-1030.

入库方式： OAI收割

来源：上海药物研究所

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