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Here, we designed, synthesized and evaluated a series of compounds as K7.2/7.3 channels (or KCNQ2/3) agonists. The new compounds were assayed in vitro for KCNQ2/3 and other receptors binding affinity. The desired compound 16 showed high activity for KCNQ2/3 (EC = 1.03 ± 0.07 μM) without acute liver injury compared to flupirtine. It demonstrated powerful dose-dependent effects in multiple analgesic models, such as chronic constriction injury (CCI, ED = 12.02 mg/kg) and streptozotocin-induced diabetic peripheral neuropathic pain (DPNP, ED = 9.63 mg/kg) models. Additionally, compound 16 showed low affinity for human ether-a-go-go-related gene (hERG), high thresholds for acute toxicity, good motor performance in the rotarod test and acceptable pharmacokinetic properties. These results suggest the potentiality of compound 16 for the treatment of neuropathic pain.