2005
DOI: 10.1124/mol.105.014803
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Molecular Modeling of Local Anesthetic Drug Binding by Voltage-Gated Sodium Channels

Abstract: Voltage-gated sodium (Na ϩ ) channels are targets for local anesthetic (LA) drugs that bind in the inner pore of the channel with affinities related to the channel gating states. Our core model of the sodium channel (P loops and S5 and S6 segments from each of the four domains) was closed because it was developed using coordinates from the KcsA channel crystallographic structure. We developed a model of the activated, open channel based on the structure of the open MthK channel, which was characterized by bend… Show more

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Cited by 169 publications
(167 citation statements)
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“…This binding site with a bound local anesthetic has been modeled within the S6 inner cavity of the rNav1.4 Na + channel by Lipkind and Fozzard (2005). Such information allows us to test whether capsaicin block of Na + currents is via the local anesthetic receptor.…”
Section: Capsaicin Blocks Na + Currents Via a Receptor That Is Distinmentioning
confidence: 99%
See 1 more Smart Citation
“…This binding site with a bound local anesthetic has been modeled within the S6 inner cavity of the rNav1.4 Na + channel by Lipkind and Fozzard (2005). Such information allows us to test whether capsaicin block of Na + currents is via the local anesthetic receptor.…”
Section: Capsaicin Blocks Na + Currents Via a Receptor That Is Distinmentioning
confidence: 99%
“…Following the experiments of Lundbaek et al (2005) and the modeling work of Lipkind and Fozzard (2005) we chose the rNav1.4 skeletal muscle Na + channels to study the blocking action of capsaicin and capsazepine. The chemical structures of these drugs are shown in Fig.…”
Section: Introductionmentioning
confidence: 99%
“…The guardedreceptor model emphasizes the dependence of hydrophilic or hydrophobic path of the drug in binding and unbinding kinetics. 38 There have been a lot of drugs 3,39,40 invented which binds with sodium channel, can be broadly divided into 2 classes, 41,42 as open state blocker and inactive state stabilizing blocker. From clinical stand point, drugs that have strong open channel blocking potency are called class 1a antiarrhythmics, such as quinidine, mexilitine and disopyramide whereas class 1b antiarrhythmics like lidocaine preferentially block peak over late current.…”
Section: Kinetics Of Drug Bindingmentioning
confidence: 99%
“…SCBIs are bigger and have more electronegative atoms than LAs like lidocaine. At physiological pH, LAs are protonated to bear a positive charge that enables the channel block by electrostatic mechanism (13,14). In contrast, SCBIs are electrically neutral non-ionizable compounds (Fig.…”
mentioning
confidence: 99%
“…Molecular interactions of LAs with mammalian sodium channels have been intensively studied (11,12). Furthermore, structural models of the Na v 1.4 channel are elaborated in which several pore-facing residues in the inner helix IVS6 contribute to the binding site of LAs (13,14). In particular, two LA-sensing residues in IVS6, i.e.…”
mentioning
confidence: 99%