E0199 is an innovative and potent KV7/NaV dual-target modulator that activates KV7 potassium channels, including KV7.2/7.3 (EC50 = 12.78 nM), KV7.2 (EC50 = 0.50 μM), and KV7.5 (EC50 = 27.14 nM), while inhibiting NaV1.7 (IC50 = 0.52 μM), NaV1.8 (IC50 = 0.24 μM), and NaV1.9 (IC50 = 0.16 μM) sodium channels. In a mouse model of chronic constriction injury (CCI) to the sciatic nerve, E0199 demonstrated potent analgesic effects without significant impact on cardiac and skeletal muscle ion channels. E0199 is applicable in studies related to neuropathic pain (NP).

NaV1.7:0.52 μM

E0199 (0.1-10 μM) influences the inactivation process of Na V 1.7, Na V 1.8, and Na V 1.9 sodium channels by promoting their inactivation and affecting the degree of inactivation curve shift, in the order: Na V 1.8 > Na V 1.9 > Na V 1.7. At concentrations of 0.03-10 μM, E0199 activates K V 7.2 to K V 7.5 potassium channels, shifting their activation curves towards hyperpolarization and thereby opening the K 7 channel, with efficacy order K V 7.2/7.3 > K V 7.2 > K V 7.5 > K V 7.4. Additionally, E0199 (1-10 μM) significantly alters the discharge parameters of action potentials (AP) in dorsal root ganglion (DRG) neurons of rats with chronic constriction injury (CCI) of the sciatic nerve, in a dose-dependent manner, affecting threshold, basal strength, amplitude, and resting membrane potential (RMP).

E0199 (administered intraperitoneally at doses of 1, 5, and 20 mg/kg, once daily from day 11 to 30 post-modeling) significantly alleviates thermal, mechanical, and cold hypersensitivity in a chronic constriction injury (CCI) mouse model of the sciatic nerve. Additionally, it enhances movement in the central zone of an open field and improves exploratory behavior in the elevated plus maze.