4-methyl-3-aminopyridine: A novel active blocker of voltage-gated potassium ion channels in the central nervous system.

Aminopyridines, including 4-aminopyridine (4AP), 3,4-diaminopyridine, and [18F]3-fluoro-4-aminopyridine, are voltage-gated potassium (KV) channel blockers used clinically to enhance conduction in neurological disorders and to image demyelination by positron emission tomography (PET). Developing new aminopyridines may yield improved therapeutics or imaging agents. Here, we characterized the physicochemical properties (pKa, logD), KV channel-blocking activity, toxicity (LD50), and pharmacokinetics of a novel compound, 4-methyl-3-aminopyridine (4Me3AP). 4Me3AP was less basic and more lipophilic than 4AP and showed greater blocking potency across multiple KV channels expressed in Xenopus oocytes. In mice, 4Me3AP exhibited lower acute toxicity (LD50 = 29.3 mg/kg) than 4AP (LD50 = 12.7 mg/kg) and a longer plasma half-life. These findings indicate that 4Me3AP is a potent KV channel blocker with favorable pharmacological properties, supporting its potential for symptomatic treatment of demyelinating diseases.