Nav1.7 Modulator Bearing a 3-Hydroxyindole Backbone Holds the Potential to Reverse Neuropathic Pain

Wang, Yuwei1; Shu, Jirong2; Yang, Haoyi1; Hong, Kemiao; Yang, Xiangji2; Guo, Weijie1,2; Fang, Jie1; Li, Fuyi1; Liu, Tao1; Shan, Zhiming3,4,5; Shi, Taoda2; Cai, Song1; Zhang, Jian1

2024-03-07

10.1021/acschemneuro.3c00353

ACS CHEMICAL NEUROSCIENCE   影响因子和分区

1948-7193

Chronic pain is a growing global health problem affecting at least 10% of the world's population. However, current chronic pain treatments are inadequate. Voltage-gated sodium channels (Navs) play a pivotal role in regulating neuronal excitability and pain signal transmission and thus are main targets for nonopioid painkiller development, especially those preferentially expressed in dorsal root ganglial (DRG) neurons, such as Nav1.6, Nav1.7, and Nav1.8. In this study, we screened in virtual hits from dihydrobenzofuran and 3-hydroxyoxindole hybrid molecules against Navs via a veratridine (VTD)-based calcium imaging method. The results showed that one of the molecules, 3g, could inhibit VTD-induced neuronal activity significantly. Voltage clamp recordings demonstrated that 3g inhibited the total Na+ currents of DRG neurons in a concentration-dependent manner. Biophysical analysis revealed that 3g slowed the activation, meanwhile enhancing the inactivation of the Navs. Additionally, 3g use-dependently blocked Na+ currents. By combining with selective Nav inhibitors and a heterozygous expression system, we demonstrated that 3g preferentially inhibited the TTX-S Na+ currents, specifically the Nav1.7 current, other than the TTX-R Na+ currents. Molecular docking experiments implicated that 3g binds to a known allosteric site at the voltage-sensing domain IV(VSDIV) of Nav1.7. Finally, intrathecal injection of 3g significantly relieved mechanical pain behavior in the spared nerve injury (SNI) rat model, suggesting that 3g is a promising candidate for treating chronic pain.

Nav1.7 pain voltage-gated sodium channels 3g synthesized compounds nonopioid

SCI

英语

其他

National Natural Science Foundation of China["82201376","82003592","82001188"] ; Natural Science Foundation of Guangdong Province[2021A1515011129] ; Science and Technology Innovative Commission of Shenzhen[20200812143116001] ; Science and Technology Planning Project of Shenzhen Municipality[JCYJ20190807154401665] ; Clinical Cultivation Program of Shenzhen People's Hospital[SYLCYJ202104]

Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology

Biochemistry & Molecular Biology ; Chemistry, Medicinal ; Neurosciences

WOS:001181205300001

AMER CHEMICAL SOC

Web of Science

1.Shenzhen Univ, Hlth Sci Ctr, Sch Pharmaceut Sci, Shenzhen 518060, Peoples R China
2.Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangdong Chiral Drug Engn Lab, Guangzhou 510000, Peoples R China
3.Southern Univ Sci & Technol, Affiliated Hosp 1, Dept Anesthesiol, Shenzhen Peoples Hosp, Shenzhen 518020, Peoples R China
4.Jinan Univ, Clin Med Coll 2, Shenzhen 518020, Peoples R China
5.Univ Hong Kong, Lab & Clin Res Inst Pain, Li Ka Shing Fac Med, Sch Clin Med,Dept Anaesthesiol, Hong Kong 999077, Peoples R China

Wang, Yuwei,Shu, Jirong,Yang, Haoyi,et al. Nav1.7 Modulator Bearing a 3-Hydroxyindole Backbone Holds the Potential to Reverse Neuropathic Pain[J]. ACS CHEMICAL NEUROSCIENCE,2024,15(6).

Wang, Yuwei.,Shu, Jirong.,Yang, Haoyi.,Hong, Kemiao.,Yang, Xiangji.,...&Zhang, Jian.(2024).Nav1.7 Modulator Bearing a 3-Hydroxyindole Backbone Holds the Potential to Reverse Neuropathic Pain.ACS CHEMICAL NEUROSCIENCE,15(6).

Wang, Yuwei,et al."Nav1.7 Modulator Bearing a 3-Hydroxyindole Backbone Holds the Potential to Reverse Neuropathic Pain".ACS CHEMICAL NEUROSCIENCE 15.6(2024).