title: Current understanding of the mechanism of action of the antiepileptic drug lacosamide.
abstract: The antiepileptic drug lacosamide [(R)-2-acetamido-N-benzyl-3-methoxypropanamide], a chiral functionalized amino acid, was originally identified by virtue of activity in the mouse and rat maximal electroshock (MES) test. Attention was drawn to lacosamide because of its high oral potency and stereoselectivity. Lacosamide is also active in the 6 Hz seizure model but inactive against clonic seizures in rodents induced by subcutaneous pentylenetetrazol, bicuculline and picrotoxin. It is also ineffective in genetic models of absence epilepsy. At doses greater than those required to confer protection in the MES test, lacosamide inhibits behavioral and electrographic seizures in hippocampal kindled rats. It also effectively terminates seizures in the rat perforant path stimulation status epilepticus model when administered early after the onset of seizures. Lacosamide does not exhibit antiepileptogenic effects in kindling or post-status epilepticus models. The profile of lacosamide in animal seizure and epilepsy models is similar to that of sodium channel blocking antiepileptic drugs, such as phenytoin and carbamazepine. However, unlike these agents, lacosamide does not affect sustained repetitive firing (SRF) on a time scale of hundreds of milliseconds or affect fast inactivation of voltage-gated sodium channels; however, it terminates SRF on a time scale of seconds by an apparent effect on sodium channel slow inactivation. Lacosamide shifts the slow inactivation curve to more hyperpolarized potentials and enhances the maximal fraction of channels that are in the slow inactivated state. Currently, lacosamide is the only known antiepileptic drug in clinical practice that exerts its anticonvulsant activity predominantly by selectively enhancing slow sodium channel inactivation.
authors.affiliation: Department of Neurology, University of California, Davis, Sacramento, CA, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rogawski
authors.affiliation: UCB Pharma, Brussels, Belgium.
authors.forename: Azita
authors.initials: A
authors.lastname: Tofighy
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
authors.affiliation: UCB Pharma, Braine L'Alleud, Belgium.
authors.forename: Alain
authors.initials: A
authors.lastname: Matagne
authors.affiliation: UCB Pharma, Braine L'Alleud, Belgium. Electronic address: Christian.Wolff@ucb.com.
authors.forename: Christian
authors.initials: C
authors.lastname: Wolff
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D006801:Humans; D000078334:Lacosamide; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D061567:Voltage-Gated Sodium Channel Blockers; D000078334:Lacosamide
keywords: Drug; Drug screening; Epilepsy model; Mode of action; Sodium channel