Papers of the Week

Genetic loss-of-function mutations of the Na1.7 channel, abundantly expressed in peripheral nociceptive neurons, cause congenital insensitivity to pain in humans, indicating that selective inhibition of the channel may lead to potential therapy for pain disorders. In this study, we investigated a novel compound, 5-chloro-N-(cyclopropylsulfonyl)-2-fluoro-4-(2-(8-(furan-2-ylmethyl)-8-azaspiro [4.5] decan-2-yl) ethoxy) benzamide (QLS-278) that inhibits Na1.7 channels and exhibits antinociceptive activity. Compound QLS-278 exhibits inactivation- and concentration-dependent inhibition of macroscopic currents of Na1.7 channels stably expressed in HEK293 cells with an IC of 1.2 ± 0.2 μM. QLS-278 causes a hyperpolarization shift of the channel inactivation and delays recovery from inactivation, without any noticeable effect on voltage-dependent activation. In mouse dorsal root ganglion neurons, QLS-278 suppresses native tetrodotoxin-sensitive Na currents and also reduces neuronal firings. Moreover, QLS-278 dose-dependently relieves neuropathic pain induced by spared nerve injury and inflammatory pain induced by formalin without significantly altering spontaneous locomotor activity in mice. Therefore, our identification of the novel compound QLS-278 may hold developmental potential in chronic pain treatment. SIGNIFICANCE STATEMENT: QLS-278, a novel voltage-gated sodium Na1.7 channel blocker, inhibits native tetrodotoxin-sensitive Na current and reduces action potential firings in dorsal root ganglion sensory neurons. QLS-278 also exhibits antinociceptive activity in mouse models of pain, demonstrating the potential for the development of a chronic pain treatment.