Key result
3-methyl-4-aminopyridine (3Me4AP) was approximately 7-fold more potent than 4AP at blocking voltage-gated potassium channels, while methoxy and trifluoromethyl derivatives were 3- to 4-fold less potent.
Why the study?
Following findings that a radiofluorinated 4AP analog binds to KV1 channels for PET imaging of demyelinated lesions, novel 4AP derivatives were investigated as potential candidates for PET imaging or therapy.
Answers are grounded in this paper and cite their sources.
The novel derivative 3-methyl-4-aminopyridine is a highly potent K+ channel blocker, suggesting potential as a PET imaging or therapeutic agent for demyelinating diseases.
Abstract 4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (K V 1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [ 18 F]3F4AP, a radiofluorinated analog of 4AP, also binds to K V 1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate three novel 4AP derivatives containing methyl (-CH 3 ), methoxy (-OCH 3 ) and trifluoromethyl (-CF 3 ) in the 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (p K a and logD) and analyzed their ability to block Shaker K + channel under different voltage and pH conditions. Our results demonstrate that all three 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, whereas the methoxy (3MeO4AP) and trifluoromethyl (3CF 3 4AP) containing compounds were about 3- to 4-fold less potent than 4AP, respectively. These results suggest that these novel derivatives are potential candidates for therapy and imaging.
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Rodríguez-Rangel et al. (2019) studied Multiple sclerosis (preclinical/in vitro). 4-aminopyridine derivatives (3Me4AP, 3MeO4AP, 3CF34AP) vs. 4-aminopyridine (4AP) was evaluated on Ability to block Shaker K+ channel (7-fold more potent (3Me4AP); 3- to 4-fold less potent (3MeO4AP, 3CF34AP)). 3-methyl-4-aminopyridine (3Me4AP) was approximately 7-fold more potent than 4AP at blocking voltage-gated potassium channels, while methoxy and trifluoromethyl derivatives were 3- to 4-fold less potent.
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