CNV1014802 Rescues the Paroxysmal Extreme Pain Disorders Nav1.7 Mutants by Restoring Impaired Inactivation

Abstract

Voltage-gated sodium channel subtype Nav1.7 plays a critical role in pain reception and represents a promising target for pain relief. CNV1014802, a selective Nav1.7 inhibitor developed by Convergence Pharmaceuticals, has recently completed its phase II clinical trial in the treatment of trigeminal neuralgia. However, the inhibitory features and other potential applications of CNV1014802 remain elusive. Firstly, the effects of CNV on kinetics of Nav1.7 were characterized using whole-cell patch clamp. We find that holding potentials predominantly determines its inhibition potency on Nav1.7 channels. The IC50 values are 1.77 ± 0.28 µM and 71.66 ± 11.93 µM, respectively, when holding potentials are set at −70 mV or −120 mV. Moreover, CNV1014802 significantly hyperpolarizes channel inactivation whereas does not affect the channel activation. In addition, CNV1014802 accelerates the inactivation onset and delays the recovery from inactivation. Finally, CNV1014802 is capable of rescuing Nav1.7 mutations casual of paroxysmal extreme pain disorders (PEPD) by restoring their impaired inactivation to that of wild-type channels. Our study indicates that CNV1014802 may benefit hereditary painful disorder patients with Nav1.7 mutations impairing inactivation.Keywords: Nav1.7, CNV1014802, Inactivation, Paroxysmal extreme pain disorders