Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants

Local anesthetics, antiarrhythmics, and anticonvulsants include both charged and electroneutral compounds that block voltage-gated sodium channels. Prior studies have revealed a common drug-binding region within the pore, but details about the binding sites and mechanism of block remain unclear. Her...

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Vydané v:The Journal of general physiology Ročník 149; číslo 4; s. 465
Hlavní autori: Tikhonov, Denis B, Zhorov, Boris S
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 03.04.2017
Predmet:
Acetamides - pharmacology
Anesthetics, Local - pharmacology
Animals
Anti-Arrhythmia Agents - pharmacology
Anticonvulsants - pharmacology
Benzhydryl Compounds - pharmacology
Binding Sites
Carbamazepine - pharmacology
Cocaine - pharmacology
Humans
Lacosamide
Lamotrigine
Lidocaine - analogs & derivatives
Lidocaine - pharmacology
Molecular Docking Simulation
NAV1.4 Voltage-Gated Sodium Channel - chemistry
NAV1.4 Voltage-Gated Sodium Channel - metabolism
Phenols - pharmacology
Phenytoin - pharmacology
Piperazines - pharmacology
Protein Binding
Pyrimidines - pharmacology
Quinidine - pharmacology
Sodium Channel Blockers - pharmacology
Triazines - pharmacology
ISSN:1540-7748, 1540-7748
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Shrnutí:Local anesthetics, antiarrhythmics, and anticonvulsants include both charged and electroneutral compounds that block voltage-gated sodium channels. Prior studies have revealed a common drug-binding region within the pore, but details about the binding sites and mechanism of block remain unclear. Here, we use the x-ray structure of a prokaryotic sodium channel, NavMs, to model a eukaryotic channel and dock representative ligands. These include lidocaine, QX-314, cocaine, quinidine, lamotrigine, carbamazepine (CMZ), phenytoin, lacosamide, sipatrigine, and bisphenol A. Preliminary calculations demonstrated that a sodium ion near the selectivity filter attracts electroneutral CMZ but repels cationic lidocaine. Therefore, we further docked electroneutral and cationic drugs with and without a sodium ion, respectively. In our models, all the drugs interact with a phenylalanine in helix IVS6. Electroneutral drugs trap a sodium ion in the proximity of the selectivity filter, and this same site attracts the charged group of cationic ligands. At this position, even small drugs can block the permeation pathway by an electrostatic or steric mechanism. Our study proposes a common pharmacophore for these diverse drugs. It includes a cationic moiety and an aromatic moiety, which are usually linked by four bonds.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1540-7748
1540-7748
DOI:10.1085/jgp.201611668