Pain treatment presents an unmet medical need. The voltage-gated sodium channel Nav1.7 is abundantly expressed in peripheral nociceptive neurons. Genetic studies demonstrate that the gain-of-function mutations of Nav1.7 can cause hyperalgesia, while its loss-of-function mutations can cause congenital insensitivity to pain (CIP). These observations suggest that pharmacological inhibition of Nav1.7 may hold therapeutic potential for chronic pain. Based on a drug candidate ralfinamide as Nav1.7 inhibitor in phase III clinical trial, a novel small molecule QLS-127 was synthesized and identified. Here, we report that QLS-127 inhibits Nav1.7 channel and exhibits antinociceptive activity. Whole-cell patch-clamp recordings of HEK293 cells stably expressing Nav1.7 reveal that QLS-127 inhibits the peak current of Nav1.7 in a dose-dependent manner (IC₅₀ = 2.9 ± 0.8 uM), and its potency was about 12-fold batter than that of ralfinamide (IC₅₀ = 35.2 ± 2.8 uM). In vivo test shows that QLS-127 (5, 10, 20 mg/kg, i.p.) dose-dependently alleviated spared nerve injury (SNI)-induced neuropathic pain in mice. In addition, QLS-127 (20 mg/kg, i.p.) had no obvious effect on the locomotor activity. These results suggest that QLS-127-mediated antinociceptive activity is likely resulted from the inhibition of Nav channels, but not from the sedation effect. Furthermore, the Nav1.7 channel inactivation dynamics and selectivity evaluation of QLS-127 are in progress.

 

Nav1.7,inhibitor,antinociception,QLS-127,therapeutic target