Seeking a mechanism of action for the novel anticonvulsant lacosamide.

Lacosamide (LCM) is anticonvulsant in animal models and is in phase 3 assessment for epilepsy and neuropathic pain. Here we seek to identify cellular actions for the new drug and effects on recognised target sites for anticonvulsant drugs. Radioligand binding and electrophysiology were used to study the effects of LCM at well-established mammalian targets for clinical anticonvulsants. 10 microM LCM did not bind with high affinity to a plethora of rodent, guinea pig or human receptor sites including: AMPA; Kainate; NMDA (glycine/PCP/MK801); GABA(A) (muscimol/benzodiazepine); GABA(B); adenosine A1,2,3; alpha1, alpha2; beta1, beta2; M1,2,3,4,5; H1,2,3; CB1,2; D1,2,3,4,5; 5HT1A,1B,2A,2C,3,5A,6,7 and KATP. Weak displacement (25%) was evident at batrachotoxin site 2 on voltage gated Na+ channels. LCM did not inhibit neurotransmitter transport mechanisms for norepinephrine, dopamine, 5-HT or GABA, nor did it inhibit GABA transaminase. LCM at 100 microM produced a significant reduction in the incidence of excitatory postsynaptic currents (EPSC's) and inhibitory postsynaptic currents (IPSC's) in cultured cortical cells and blocked spontaneous action potentials (EC50 61 microM). LCM did not alter resting membrane potential or passive membrane properties following application of voltage ramps between -70 to +20 mV. The voltage-gated sodium channel (VGSC) blocker phenytoin potently blocked sustained repetitive firing (SRF) but, in contrast, 100 microM LCM failed to block SRF. No effect was observed on voltage-clamped Ca2+ channels (T-, L-, N- or P-type). Delayed-rectifier or A-type potassium currents were not modulated by LCM (100 microM). LCM did not mimic the effects of diazepam as an allosteric modulator of GABA(A) receptor currents, nor did it significantly modulate evoked excitatory neurotransmission mediated by NMDA or AMPA receptors (n > or = 5). Evidently LCM perturbs excitability in primary cortical cultures but does not appear to do so via a high-affinity interaction with an acknowledged recognition site on a target for existing antiepileptic drugs.