Development and characterization of novel derivatives of the antiepileptic drug lacosamide that exhibit far greater enhancement in slow inactivation of voltage-gated sodium channels

Yuying Wang, Ki Duk Park, Christophe Salomé, Sarah M. Wilson, James P. Stables, Rihe Liu, Rajesh Khanna, Harold Kohn

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

The novel antiepileptic drug (R)-N-benzyl 2-acetamido-3-methoxypropionamide ((R)-lacosamide, Vimpat ((R)-1)) was recently approved in the United States and Europe for adjuvant treatment of partial-onset seizures in adults. (R)-1 preferentially enhances slow inactivation of voltage-gated Na+ currents, a pharmacological process relevant in the hyperexcitable neuron. We have advanced a strategy to identify lacosamide binding partners by attaching affinity bait (AB) and chemical reporter (CR) groups to (R)-1 to aid receptor detection and isolation. We showed that select lacosamide AB and AB&CR derivatives exhibited excellent activities similar to (R)-1 in the maximal electroshock seizure model in rodents. Here, we examined the effect of these lacosamide AB and AB&CR derivatives and compared them with (R)-1 on Na + channel function in central nervous system (CNS) catecholaminergic (CAD) cells. Using whole-cell patch clamp electrophysiology, we demonstrated that the test compounds do not affect the Na+ channel fast inactivation process, that they were far better modulators of slow inactivation than (R)-1, and that modulation of the slow inactivation process was stereospecific. The lacosamide AB agents that contained either an electrophilic isothiocyanate ((R)-5) or a photolabile azide ((R)-8) unit upon AB activation gave modest levels of permanent Na+ channel slow inactivation, providing initial evidence that these compounds may have covalently reacted with their cognate receptor(s). Our findings support the further use of these agents to delineate the (R)-1-mediated Na+ channel slow inactivation process.

Original languageEnglish (US)
Pages (from-to)90-106
Number of pages17
JournalACS Chemical Neuroscience
Volume2
Issue number2
DOIs
StatePublished - Feb 16 2011

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Keywords

  • Lacosamide
  • affinity bait
  • slow inactivation
  • sodium channel

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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