Lacosamide

Perucca, Emilio; Yasothan, Uma; Clincke, G.; Kirkpatrick, Peter J.

doi:10.1038/nrd2764

Cited by 102 publications

(85 citation statements)

References 13 publications

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“…The novel antiepileptic drug lacosamide ((R)-N-benzyl 2-acetamido-3-methoxypropionamide) (LCM, 4 Vimpat) (1) has been recently approved in the U.S. and Europe for adjunctive treatment of partial-onset seizures in adults (2)(3)(4) and can be effective in cases of refractory epilepsy (5). Experimental data suggest two modes of action.…”

Section: The Anti-epileptic Drug (R)-lacosamide ((2r)-2-(acetylamino)mentioning

confidence: 99%

In Silico Docking and Electrophysiological Characterization of Lacosamide Binding Sites on Collapsin Response Mediator Protein-2 Identifies a Pocket Important in Modulating Sodium Channel Slow Inactivation

Wang

Brittain

Jarecki

et al. 2010

Journal of Biological Chemistry

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The anti-epileptic drug (R)-lacosamide ((2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide (LCM)) modulates voltage-gated sodium channels (VGSCs) by preferentially interacting with slow inactivated sodium channels, but the observation that LCM binds to collapsin response mediator protein 2 (CRMP-2) suggests additional mechanisms of action for LCM. We postulated that CRMP-2 levels affects the actions of LCM on VGSCs. CRMP-2 labeling by LCM analogs was competitively displaced by excess LCM in rat brain lysates. Manipulation of CRMP-2 levels in the neuronal model system CAD cells affected slow inactivation of VGSCs without any effects on other voltage-dependent properties. In silico docking was performed to identify putative binding sites in CRMP-2 that may modulate the effects of LCM on VGSCs. These studies identified five cavities in CRMP-2 that can accommodate LCM. CRMP-2 alanine mutants of key residues within these cavities were functionally similar to wildtype CRMP-2 as assessed by similar levels of enhancement in dendritic complexity of cortical neurons. Next, we examined the effects of expression of wild-type and mutant CRMP-2 constructs on voltage-sensitive properties of VGSCs in CAD cells: 1) steady-state voltage-dependent activation and fastinactivation properties were not affected by LCM, 2) CRMP-2 single alanine mutants reduced the LCM-mediated effects on the ability of endogenous Na ؉ channels to transition to a slow inactivated state, and 3) a quintuplicate CRMP-2 alanine mutant further decreased this slow inactivated fraction. Collectively, these results identify key CRMP-2 residues that can coordinate LCM binding thus making it more effective on its primary clinical target.

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Section: The Anti-epileptic Drug (R)-lacosamide ((2r)-2-(acetylamino)mentioning

confidence: 99%

In Silico Docking and Electrophysiological Characterization of Lacosamide Binding Sites on Collapsin Response Mediator Protein-2 Identifies a Pocket Important in Modulating Sodium Channel Slow Inactivation

Wang

Brittain

Jarecki

et al. 2010

Journal of Biological Chemistry

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“…13 One of these compounds, (R)-N-benzyl 2-acetamido-3-methoxypropionamide 6 (lacosamide, (R)-2), is a first-in-class AED marketed in 34 countries, including the United States. 14 Studies have shown that (R)-2 preferentially transitioned voltage-gated Na + channels (VGSCs) to the slow inactivation state without affecting fast inactivation. 15−17 Na + channel slow inactivation promotion is a powerful mechanism to control the hyperexcitable neuron in the epileptic patient, where neurons are either rapidly firing or in a sustained, depolarized state.…”

Section: Introductionmentioning

confidence: 99%

Identification of the Benzyloxyphenyl Pharmacophore: A Structural Unit That Promotes Sodium Channel Slow Inactivation

King

Yang

Wang

et al. 2012

ACS Chem. Neurosci.

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Four compounds that contained the N-benzyl 2-amino-3-methoxypropionamide unit were evaluated for their ability to modulate Na+ currents in catecholamine A differentiated CAD neuronal cells. The compounds differed by the absence or presence of either a terminal N-acetyl group or a (3-fluoro)benzyloxy moiety positioned at the 4′-benzylamide site. Analysis of whole-cell patch-clamp electrophysiology data showed that the incorporation of the (3-fluoro)benzyloxy unit, to give the (3-fluoro)benzyloxyphenyl pharmacophore, dramatically enhanced the magnitude of Na+ channel slow inactivation. In addition, N-acetylation markedly increased the stereoselectivity for Na+ channel slow inactivation. Furthermore, we observed that Na+ channel frequency (use)-dependent block was maintained upon inclusion of this pharmacophore. Confirmation of the importance of the (3-fluoro)benzyloxyphenyl pharmacophore was shown by examining compounds where the N-benzyl 2-amino-3-methoxypropionamide unit was replaced by a N-benzyl 2-amino-3-methylpropionamide moiety, as well as examining a series of compounds that did not contain an amino acid group but retained the pharmacophore unit. Collectively, the data indicated that the (3-fluoro)benzyloxyphenyl unit is a novel pharmacophore for the modulation of Na+ currents.

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“…Lacosamide is a novel functionalized amino acid that enhances inactivation of voltagegated sodium channels (Curia et al, 2009;Perucca et al, 2008b). Lacosamide was approved in Europe in 2008 for partial-onset seizures in patients 16 years and older (Chung et al, 2010).…”

Section: Lacosamidementioning

confidence: 99%

Therapeutic Drug Monitoring of Antiepileptic Medications

Krasowski¹

2011

Novel Treatment of Epilepsy

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Lacosamide

Cited by 102 publications

References 13 publications

In Silico Docking and Electrophysiological Characterization of Lacosamide Binding Sites on Collapsin Response Mediator Protein-2 Identifies a Pocket Important in Modulating Sodium Channel Slow Inactivation

In Silico Docking and Electrophysiological Characterization of Lacosamide Binding Sites on Collapsin Response Mediator Protein-2 Identifies a Pocket Important in Modulating Sodium Channel Slow Inactivation

Identification of the Benzyloxyphenyl Pharmacophore: A Structural Unit That Promotes Sodium Channel Slow Inactivation

Therapeutic Drug Monitoring of Antiepileptic Medications

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