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Papers of the Week

Papers: 2 Mar 2024 - 7 Mar 2024

2024 Mar 06

ACS Chem Neurosci


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


Wang Y, Shu J, Yang H, Hong K, Yang X, Guo W, Fang J, Li F, Liu T, Shan Z, Shi T, Cai S, Zhang J


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, , could inhibit VTD-induced neuronal activity significantly. Voltage clamp recordings demonstrated that inhibited the total Na currents of DRG neurons in a concentration-dependent manner. Biophysical analysis revealed that slowed the activation, meanwhile enhancing the inactivation of the Navs. Additionally, use-dependently blocked Na currents. By combining with selective Nav inhibitors and a heterozygous expression system, we demonstrated that preferentially inhibited the TTX-S Na currents, specifically the Nav1.7 current, other than the TTX-R Na currents. Molecular docking experiments implicated that binds to a known allosteric site at the voltage-sensing domain IV(VSDIV) of Nav1.7. Finally, intrathecal injection of significantly relieved mechanical pain behavior in the spared nerve injury (SNI) rat model, suggesting that is a promising candidate for treating chronic pain.