Lacosamide

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

doi:10.1038/nrd2764

Cited by 101 publications

(85 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…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.

View full text Add to dashboard Cite

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.

show abstract

“…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

View full text Add to dashboard Cite

Lacosamide

Cited by 101 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

Contact Info

Product

Resources

About