Biology subjects

Sanchez-Rodriguez, J. E.

Publications and source records attributed to Sanchez-Rodriguez, J. E..

4 recordsLinked to original sources

bioRxiv2026

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 PET. Developing new aminopyridines may yield improved therapeutics or imaging agents. Here, we characterized the physicochemical properties (pKa, log D), 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.

biochemistry↗

bioRxiv2023

Chemical and biophysical characterization of novel potassium channel blocker 3-fluoro-5-methylpyridin-4-amine

4-aminopyridine (4AP) is a potassium (K+) channel blocker used clinically to improve walking in people with multiple sclerosis (MS). 4AP binds to exposed K+ channels in demyelinated axons, reducing the leakage of intracellular K+ and enhancing impulse conduction. Multiple derivatives of 4AP capable of blocking K+ channels have been reported including three radiolabeled with positron emitting isotopes for imaging demyelinated lesions using positron emission tomography (PET). Here, we describe 3-fluoro-5-methylpyridin-4-amine (5Me3F4AP), a novel K+ channel blocker with potential application in PET. 5Me3F4AP has comparable potency to 4AP and the PET tracer 3-fluoro-4-aminopyridine (3F4AP). Compared to 3F4AP, 5Me3F4AP is more lipophilic (logD = 0.664 {+/-} 0.005 vs. 0.414 {+/-} 0.002) and slightly more basic (pKa = 7.46 {+/-} 0.01 vs. 7.37 {+/-} 0.07). In addition, 5Me3F4AP appears to be more permeable to an artificial brain membrane and more stable towards oxidation by the cytochrome P450 enzyme family 2 subfamily E member 1 (CYP2E1), responsible for the metabolism of 4AP and 3F4AP. Taken together, 5Me3F4AP has promising properties for PET imaging warranting additional investigation. Significance StatementThe PET tracer [18F]3-fluoro-4-aminopyridine ([18F]3F4AP) binds to K+ channels in demyelinated axons and has shown promise for imaging demyelinated lesions in animal models. However, its use in humans may be compromised due to rapid metabolism. Thus, a novel 3F4AP derivative amenable to labeling with fluorine-18 was designed and evaluated in vitro. The results indicate that 5-methyl-3F4AP exhibits high binding affinity, good physicochemical properties and slower oxidation by CYP2E1 than 3F4AP, making it a promising candidate for further PET studies.

pharmacology and toxicology↗

bioRxiv2020

ELECTRO-STERIC MECHANISM OF CLC-2 CHLORIDE CHANNEL ACTIVATION

Two-pore voltage-gated CLC chloride channels control neuronal and muscle excitability. They share a dimeric structure but their activation mechanism remains unresolved. Here we determine the step-by-step activation mechanism of the broadly expressed CLC-2 channel using homology modelling, molecular dynamic simulations and functional studies. We establish that a two-leaf gate formed by Tyr561-H2O-Glu213 flanked by Lys568/Glu174 and Lys212 closes the canonical pore. Activation begins when a hyperpolarization-propelled intracellular chloride occupies the pore and splits Tyr561-H2O-Glu213 by electrostatic/steric repulsion. Unrestrained Glu213 rotates outwardly to bind Lys212 but the pore remains closed. Protonation breaks the Glu213-Lys212 interaction while another chloride occupies the pore thus catalysing chloride exit via Lys212. Also, we found that the canonical pore is uncoupled from a cytosolic cavity by a Tyr561-containing hydrophobic gate that prevents Glu213 protonation by intracellular protons. Our data provide atomistic details about CLC-2 activation but this mechanism might be common to other CLC channels.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2019

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

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 three novel 4AP derivatives containing methyl (-CH3), methoxy (-OCH3) and trifluoromethyl (-CF3) in the 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (pKa 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 (3CF34AP) 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.

biophysics↗