Structure-activity relationship studies of four novel 4-aminopyridine K+ channel blockers

4-氨基吡啶 钾通道阻滞剂 三氟甲基 化学 钾通道 亲脂性 药理学 电压门控钾通道 地昔帕明 立体化学 内科学 医学 有机化学 烷基 海马体 抗抑郁药
作者
Sofia Rodríguez-Rangel,Alyssa D. Bravin,Karla M. Ramos‐Torres,Pedro Brugarolas,Jorge E. Sánchez‐Rodríguez
出处
期刊:Scientific Reports [Springer Nature]
卷期号:10 (1) 被引量:32
标识
DOI:10.1038/s41598-019-56245-w
摘要

4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (KV1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [18F]3F4AP, a radiofluorinated analog of 4AP, also binds to KV1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate four novel 4AP derivatives containing methyl (-CH3), methoxy (-OCH3) as well as trifluoromethyl (-CF3) in the 2 and 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (basicity and lipophilicity) and analyzed their ability to block Shaker K+ channel under different voltage and pH conditions. Our results demonstrate that three of the four derivatives are able to block voltage-gated potassium channels. Specifically, 3-methyl-4-aminopyridine (3Me4AP) was found to be approximately 7-fold more potent than 4AP and 3F4AP; 3-methoxy- and 3-trifluoromethyl-4-aminopyridine (3MeO4AP and 3CF34AP) were found to be about 3- to 4-fold less potent than 4AP; and 2-trifluoromethyl-4-AP (2CF34AP) was found to be about 60-fold less active. These results suggest that these novel derivatives are potential candidates for therapy and imaging.
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