Recent Advances in the Medicinal Chemistry of Sodium Channel Blockers and their Therapeutic Potential

Zuliani, Valentina; Patel, Manoj K.; Fantini, Marco; Rivara, Mirko

doi:10.2174/156802609788317856

Cited by 39 publications

(26 citation statements)

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“…Sodium channel inhibitors exhibit a wide range of chemical moieties, but common to most of them is the presence of a phenyl ring connected to a basic nitrogen, with some combination of aromatic and aliphatic decorations [6], [7]. Neutral local anesthetics are known to be able to block and leave resting sodium channels when applied from either side of the membrane, a process known as ‘tonic block’.…”

Section: Introductionmentioning

confidence: 99%

“…Most sodium channel blocking drugs target all subtypes, but the development of selective channel blockers would allow a new range of clinical applications and a decrease in side effects [7]. For example, there is significant interest in increasing the specificity of drugs for the channel subtypes found in pain receptor neurons as a way to combat chronic pain [10], [11].…”

Section: Introductionmentioning

confidence: 99%

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Locating the Route of Entry and Binding Sites of Benzocaine and Phenytoin in a Bacterial Voltage Gated Sodium Channel

Martin

Corry

2014

PLoS Comput Biol

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Sodium channel blockers are used to control electrical excitability in cells as a treatment for epileptic seizures and cardiac arrhythmia, and to provide short term control of pain. Development of the next generation of drugs that can selectively target one of the nine types of voltage-gated sodium channel expressed in the body requires a much better understanding of how current channel blockers work. Here we make use of the recently determined crystal structure of the bacterial voltage gated sodium channel NavAb in molecular dynamics simulations to elucidate the position at which the sodium channel blocking drugs benzocaine and phenytoin bind to the protein as well as to understand how these drugs find their way into resting channels. We show that both drugs have two likely binding sites in the pore characterised by nonspecific, hydrophobic interactions: one just above the activation gate, and one at the entrance to the the lateral lipid filled fenestrations. Three independent methods find the same sites and all suggest that binding to the activation gate is slightly more favourable than at the fenestration. Both drugs are found to be able to pass through the fenestrations into the lipid with only small energy barriers, suggesting that this can represent the long posited hydrophobic entrance route for neutral drugs. Our simulations highlight the importance of a number of residues in directing drugs into and through the fenestration, and in forming the drug binding sites.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Locating the Route of Entry and Binding Sites of Benzocaine and Phenytoin in a Bacterial Voltage Gated Sodium Channel

Martin

Corry

2014

PLoS Comput Biol

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“…The medicinal chemistry of pre-clinical small molecule sodium channel blockers is the subject of some recent reviews [247,248]. Subtype selective sodium channel blockers have not been used clinically.…”

Section: Synthetic Compoundsmentioning

confidence: 99%

Voltage-Gated Sodium Channels: Mutations, Channelopathies and Targets

Andavan

Lemmens‐Gruber²

2011

CMC

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Voltage-gated sodium channels produce fast depolarization, which is responsible for the rising phase of the action potential in neurons, muscles and heart. These channels are very large membrane proteins and are encoded by ten genes in mammals. Sodium channels are a crucial component of excitable tissues; hence, they are a target for various neurotoxins that are produced by plants and animals for defence and protection, such as tetrodotoxin, scorpion toxins and batrachotoxin. Several mutations in various sodium channel subtypes cause multiple inherited diseases known as channelopathies. When these mutated sodium channel subtypes are expressed in various tissues, channelopathies in brain, skeletal muscle and cardiac muscle develop as well as neuropathic pain. In this review, we discuss aspects of voltage-gated sodium channel genes with an emphasis on cardiac muscle sodium channels. In addition, we report novel mutations that underlie a spectrum of diseases, such as Brugada, long QT syndrome and inherited conduction disorders. Furthermore, this review explains commonalities and differences among the channel subtypes, the channelopathies caused by the sodium channel gene mutation and the specificity of toxins and blockers of the channel subtypes.

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“…In particular, mutations in VGSC genes SCN1A (encoding the Na v 1.1 α-subunit), SCN2A (encoding the Na v 1.2 α-subunit), SCN1B (encoding the auxiliary β1-subunit), SCN3A (encoding the Na v 1.3 α-subunit) and SCN9A (encoding the Na v 1.7 α-subunit) have been reported in brain tissues of humans with epileptic syndromes. 5–8 In animal models of epilepsy, the Na v 1.6 sodium channel isoform, which is heavily expressed with the central nervous system, has been shown to be upregulated. 9,10 The Na v 1.6 isoform is thought to play an important role in controlling neuronal firing.…”

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confidence: 99%

Inhibition of NaV1.6 sodium channel currents by a novel series of 1,4-disubstituted-triazole derivatives obtained via copper-catalyzed click chemistry

Rivara

Patel

Amori

et al. 2012

Bioorganic & Medicinal Chemistry Letters

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We have synthesized and evaluated a series of 1,4-disubstituted-triazole derivatives for inhibition of the rat NaV1.6 sodium channel isoform, an isoform thought to play an important role in controlling neuronal firing. Starting from a series of 2,4(1H)-diarylimidazoles previously published, we decided to extend the SAR study by replacing the imidazole with a different heterocyclic scaffold and by varying the aryl substituents on the central aromatic ring. The 1,4-disubstituted 1,2,3-triazoles were prepared employing the copper-catalyzed azide-alkyne cycloaddition (CuAAC). Many of the new molecules were able to block the rNav1.6 currents at 10 µM by over 20%, displaying IC50 values ranging in the low micromolar, thus indicating that triazole can efficiently replace the central heterocyclic core. Moreover, the introduction of a long chain at C4 of the central triazole seems beneficial for increased rNav1.6 current block, whereas the length of N1 substituent seems less crucial for inhibition, as long as a phenyl ring is not direcly connected to the triazole. These results provide additional information on the structural features necessary for block of the voltage-gated sodium channels. These new data will be exploited in the preparation of new compounds and could result in potentially useful AEDs.

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Recent Advances in the Medicinal Chemistry of Sodium Channel Blockers and their Therapeutic Potential

Cited by 39 publications

References 0 publications

Locating the Route of Entry and Binding Sites of Benzocaine and Phenytoin in a Bacterial Voltage Gated Sodium Channel

Locating the Route of Entry and Binding Sites of Benzocaine and Phenytoin in a Bacterial Voltage Gated Sodium Channel

Voltage-Gated Sodium Channels: Mutations, Channelopathies and Targets

Inhibition of NaV1.6 sodium channel currents by a novel series of 1,4-disubstituted-triazole derivatives obtained via copper-catalyzed click chemistry

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