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

作　　者：Qiao-qiao Wang Long Wang Wen-bo Zhang Chun-ping Tang Xue-qin Chen Yue-ming Zheng Sheng Yao Zhao-bing Gao Yang Ye 

机构地区：[1]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [2]Natural Product Research Center,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [3]School of Life Science and Technology,ShanghaiTech University,Shanghai,201210,China [4]University of Chinese Academy of Sciences,Beijing,100049,China [5]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing,210046,China [6]Center for Neurological and Psychiatric Research and Drug Discovery,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [7]Zhongshan Institute of Drug Discovery,Institution for Drug Discovery Innovation,Chinese Academy of Science,Zhongshan,528400,China

出　　处：《Acta Pharmacologica Sinica》2023年第9期1768-1776,共9页中国药理学报（英文版）

基　　金：supported by the National Science Fund for Distinguished Young Scholars (grant No.81825021);the Youth Innovation Promotion Association of the Chinese Academy of Sciences (grant No.2020284);the Fund of Science and Technology Commission of Shanghai Municipality (grant No.19431906000);the Key-Area Research and Development Program of Guangdong Province (grant No.2020B0303070002);High-level New R&D Institute (grant No.2019B090904008);High-level Innovative Research Institute (grant No.2021B0909050003)from Department of Science and Technology of Guangdong Province,Zhongshan Municipal Bureau of Science and Technology;the Lingang Laboratory (LG202103-01-06,LG202103-01-05);the National Science and Technology Innovation 2030 Major Program (grant No.2021ZD0200900).

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 Kαradiation.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 IC_(50)of 0.73±0.03µM.We demonstrated that compound 2(3µM)caused dramatical shift of steady-state slow inactivation toward the hyperpolarizing direction V_(1/2)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(10μM)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.

关 键 词：Nav1.7 channel naphthylisoquinolines Ancistrocladus tectorius dorsal root ganglion neurons formalin-induced mouse inflammatory painmodel ANALGESICS 

分 类 号：R737.14[医药卫生—肿瘤]