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

• DOI: 10.1021/acschemneuro.3c00353
• Publication Date: 2024-03-07T05:15:55Z
• Authors: Yuwei Wang; Jirong Shu; Haoyi Yang; kemiao Hong; Xiangji Yang; Weijie Guo; Jie Fang; Fuyi Li; Tao Liu; Zhiming Shan; Taoda Shi; Song Cai; Jian Zhang
• Keywords: NAV1; Dorsal root ganglion; SNi; Nerve Injury

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