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

Title
Development and characterization of novel derivatives of the antiepileptic drug lacosamide that exhibit far greater enhancement in slow inactivation of voltage-gated sodium channels
Authors
Yuying Wang박기덕Christophe SalomeSarah M. WilsonJames P. StablesRihe LiuRajesh KhannaHarold Kohn
Keywords
Lacosamide; sodium channel; slow inactivation; affinity bait
Issue Date
2011-02
Publisher
ACS Chemical Neuroscience
Citation
VOL 2, NO 2, 90-106
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 lacosamideABandAB&CRderivatives 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.
URI
http://pubs.kist.re.kr/handle/201004/41152
ISSN
1948-7193
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KIST Publication > Article
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