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. 2020 Jan 9;10(1):52.
doi: 10.1038/s41598-019-56245-w.

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

Sofia Rodríguez-Rangel  1 , Alyssa D Bravin  2 , Karla M Ramos-Torres  2 , Pedro Brugarolas  3 , Jorge E Sánchez-Rodríguez  4
Affiliations

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

Sofia Rodríguez-Rangel et al. Sci Rep. .

Abstract

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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Conflict of interest statement

The University of Chicago has obtained patents related to the compounds described here where P.B. is listed as inventor (U.S. Patent: US10160695B2 and US9617215B2). Other authors declare no competing interests.

Figures

Figure 1
Figure 1
Acid-base equilibrium of 4-aminopyridine derivatives.
Figure 2
Figure 2
Inhibition of K+ currents by 4AP analogs. (A), Chemical structures of studied 4AP analogs. From left to right: 4-aminopyridine (4AP), 3-fluoro-4-aminopyridine (3F4AP), 3-methyl-4-aminopyridine (3Me4AP), 3-methoxy-4-aminopyridine (3MeO4AP), 3-trifluoromethyl-4-aminopyridine (3CF34AP), 2-trifluoromethyl-4-aminopyridine (2CF34AP). (B), Representative recordings of K+ current acquired from four to six different oocytes expressing the Shaker Kv ion channel before (gray) and after (colored line) addition of 1 mM of each 4AP analog. Currents were elicited by 50 ms depolarization steps from −100 to 50 mV in increments of 10 mV. For clarity, only the inhibition of K+ current by cumulative concentration of 4AP and derivatives recorded at 40 mV is shown. The dashed line indicates current at a value of zero and the 20 ms horizontal bar represents the time scale for all recordings. (C), Relative current as a function of the concentration of 4AP analogs obtained at 40 mV and pH 7.4. (D), IC50 of each 4AP analog and 95% confidence interval obtained by fitting the data with the Hill equation (Eq. 1). n represents the number of times each drug was tested in separate oocytes.
Figure 3
Figure 3
IC50 at 0 mV and pH dependence. Relative current vs. concentration at 0 mV at pH of 6.8 (red), 7.4 (gray) and 9.1 (blue) of: (A), 4AP, (B), 3F4AP, (C), 3Me4AP, (D), 3MeO4AP and, (E), 3CF34AP, (F), 2CF34AP. Continuous lines in panels A to E represent the fits with the Hill equation (Eq. 1). Hill parameters are summarized on Table 2.
Figure 4
Figure 4
Voltage-dependence of the IC50 for each 4AP analog. Relative current as a function of concentration of (A) 4AP, (B) 3F4AP, (C) 3Me4AP, (D) 3MeO4AP, and (E) 3CF34AP, obtained at different values of voltage. For clarity only the curves obtained at 10, 30 and 50 mV are shown. Solid lines represent the fits of the data with the Hill equation (Eq. 1). (F) IC50 vs. voltage curves of 4AP analogs determined in the range of voltage from 10 to 50 mV. IC50 values were obtained from the analysis of the data of the panels A to E. Dashed lines represent the fits with the Woodhull model (Eq. 2). Woodhull parameters δ and IC50 at V = 0 mV are shown on Table 3.
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