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Neuronal voltage‐gated potassium channels KV7.2/KV7.3 are sensitive to small‐molecule drugs such as flupirtine, even though physiological response occurs in the absence of ligands. Clinically, prolonged use of flupirtine as a pain medication is associated with rare cases of drug‐induced liver injury. Thus, safety concerns prevent a broader use of this non‐opioid and non‐steroidal analgesic in therapeutic areas with unmet medical needs such as hyperactive bladder or neonatal seizures. With the goal of studying influences of chemical structure on activity and toxicity of flupirtine, we explored modifications of the benzylamino bridge and the substitution pattern in both rings of flupirtine. Among twelve derivatives, four novel thioether derivatives showed the desired activity in cellular assays and may serve as leads for safer KV channel openers. Bridge reconstructed! Exchange of an aminoalkyl‐group of analgesic flupirtine for a sulfide bridge maintains activity at voltage‐gated potassium channels but excludes toxification via azaquinone‐diimine formation. Thio‐analogues such as 9 g could serve as leads for next generation potassium channel openers to treat pain or epilepsy. [ABSTRACT FROM AUTHOR]

Neuronal voltage-gated potassium channels K V 7.2/K V 7.3 are sensitive to small-molecule drugs such as flupirtine, even though physiological response occurs in the absence of ligands. Clinically, prolonged use of flupirtine as a pain medication is associated with rare cases of drug-induced liver injury. Thus, safety concerns prevent a broader use of this non-opioid and non-steroidal analgesic in therapeutic areas with unmet medical needs such as hyperactive bladder or neonatal seizures. With the goal of studying influences of chemical structure on activity and toxicity of flupirtine, we explored modifications of the benzylamino bridge and the substitution pattern in both rings of flupirtine. Among twelve derivatives, four novel thioether derivatives showed the desired activity in cellular assays and may serve as leads for safer K V channel openers., Competing Interests: The authors declare no conflict of interest.