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Naphthylisoquinoline alkaloids, a new structural template inhibitor of Nav1.7 sodium channel

文献类型：期刊论文

作者Wang, Qiao-qiao1,2,3,4; Wang, Long5,6; Zhang, Wen-bo5,6; Tang, Chun-ping1,2; Chen, Xue-qin1,6; Zheng, Yue-ming1,4,6; Yao, Sheng1,2,4,7; Gao, Zhao-bing1,4,5,6,7; Ye, Yang1,2,4
刊名ACTA PHARMACOLOGICA SINICA
出版日期2023-05-04
页码9
关键词Nav1.7 channel naphthylisoquinolines Ancistrocladus tectorius dorsal root ganglion neurons formalin-induced mouse inflammatory pain model analgesics
ISSN号1671-4083
DOI10.1038/s41401-023-01084-9
通讯作者Zheng, Yue-ming(zhengyueming@simm.ac.cn) ; Yao, Sheng(yaosheng@simm.ac.cn) ; Gao, Zhao-bing(zbgao@simm.ac.cn) ; Ye, Yang(yye@simm.ac.cn)
英文摘要Voltage-gated sodium channel 1.7 (Nav1.7) remains one of the most promising drug targets for pain relief. In the current study, we conducted a high-throughput screening of natural products in our in-house compound library to discover novel Nav1.7 inhibitors, then characterized their pharmacological properties. We identified 25 naphthylisoquinoline alkaloids (NIQs) from Ancistrocladus tectorius to be a novel type of Nav1.7 channel inhibitors. Their stereostructures including the linkage modes of the naphthalene group at the isoquinoline core were revealed by a comprehensive analysis of HRESIMS, 1D, and 2D NMR spectra as well as ECD spectra and single-crystal X-ray diffraction analysis with Cu Ka radiation. All the NIQs showed inhibitory activities against the Nav1.7 channel stably expressed in HEK293 cells, and the naphthalene ring in the C-7 position displayed a more important role in the inhibitory activity than that in the C-5 site. Among the NIQs tested, compound 2 was the most potent with an IC50 of 0.73 +/- 0.03 mu M. We demonstrated that compound 2 (3 mu M) caused dramatical shift of steady-state slow inactivation toward the hyperpolarizing direction (V1/ 2 values were changed from -39.54 +/- 2.77 mV to -65.53 +/- 4.39 mV, which might contribute to the inhibition of compound 2 against the Nav1.7 channel. In acutely isolated dorsal root ganglion (DRG) neurons, compound 2 (10 mu M) dramatically suppressed native sodium currents and action potential firing. In the formalin-induced mouse inflammatory pain model, local intraplantar administration of compound 2 (2, 20, 200 nmol) dose-dependently attenuated the nociceptive behaviors. In summary, NIQs represent a new type of Nav1.7 channel inhibitors and may act as structural templates for the following analgesic drug development.
WOS关键词FORMALIN TEST ; SENSORY NEURONS ; ALPHA-SUBUNIT ; NA(V)1.7 ; PAIN ; INACTIVATION ; MUTATIONS ; SCN9A
资助项目National Science Fund for Distinguished Young Scholars[81825021] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2020284] ; Fund of Science and Technology Commission of Shanghai Municipality[19431906000] ; Key-Area Research and Development Program of Guangdong Province[2020B0303070002] ; High-level New RD Institute[2019B090904008] ; Department of Science and Technology of Guangdong Province, Zhongshan Municipal Bureau of Science and Technology, the Lingang Laboratory[LG202103-01-05] ; Department of Science and Technology of Guangdong Province, Zhongshan Municipal Bureau of Science and Technology, the Lingang Laboratory[2021B0909050003] ; National Science and Technology Innovation 2030 Major Program ; [LG202103-01-06] ; [2021ZD0200900]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000982082900001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/306638]  
专题新药研究国家重点实验室
通讯作者Zheng, Yue-ming; Yao, Sheng; Gao, Zhao-bing; Ye, Yang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Nat Prod Res Ctr, Shanghai 201203, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Neurol & Psychiat Res & Drug Discovery, Shanghai 201203, Peoples R China
7.Chinese Acad Sci, Inst Drug Discovery Innovat, Zhongshan Inst Drug Discovery, Zhongshan 528400, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Qiao-qiao,Wang, Long,Zhang, Wen-bo,et al. Naphthylisoquinoline alkaloids, a new structural template inhibitor of Nav1.7 sodium channel[J]. ACTA PHARMACOLOGICA SINICA,2023:9.
APA Wang, Qiao-qiao.,Wang, Long.,Zhang, Wen-bo.,Tang, Chun-ping.,Chen, Xue-qin.,...&Ye, Yang.(2023).Naphthylisoquinoline alkaloids, a new structural template inhibitor of Nav1.7 sodium channel.ACTA PHARMACOLOGICA SINICA,9.
MLA Wang, Qiao-qiao,et al."Naphthylisoquinoline alkaloids, a new structural template inhibitor of Nav1.7 sodium channel".ACTA PHARMACOLOGICA SINICA (2023):9.

入库方式： OAI收割

来源：上海药物研究所

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