Abstracts

Seletracetam (ucb 44212) is a new pyrrolidone derivative, structurally related to levetiracetam (LEV; [italic]Keppra[reg][/italic]), which has higher affinity (pKi = 7.1) than LEV (pKi = 6.1) to the LEV-binding site (the synaptic vesicle protein 2A) and displays higher potency and efficacy than LEV, in rodent models of epilepsy. This study investigated if the mechanism(s) of action of seletracetam involves modulation of ionotropic inhibitory and/or excitatory receptors. GABA-, glycine-, NMDA-, kainic acid- and AMPA-gated currents were studied [italic]in vitro[/italic] using whole-cell patch-clamp techniques applied on cultured hippocampal neurons. Seletracetam (up to 100 [micro]M) was devoid of any direct effect on both GABA-, glycine-, kainic acid- and AMPA-gated currents. Regarding the biphasic response induced by application of NMDA, seletracetam (up to 100 [micro]M) had no effect on the peak current amplitude but reduced the amplitude of the plateau phase (IC[sub]50[/sub] value = 1.5 [plusmn] 0.8 [micro]M; maximal inhibiton at 100 [micro]M = 41% of control value). Seletracetam (up to 100 [micro]M) was unable to reverse the inhibitory effect of zinc on GABA-gated currents and showed an effect against [beta]-carboline inhibition only at 100 [micro]M. In contrast, a very potent ability to reverse the reduction by these negative allosteric modulators was observed with glycine-gated currents. Thus, seletracetam totally reversed the inhibitory effect of zinc and [beta]-carboline on glycine-gated currents from concentrations of 10 pM and 1 [micro]M, respectively. The results of the present study show that seletracetam is devoid of any direct action on both inhibitory and excitatory neurotransmission with the exception of a minor inhibition of the plateau phase of the NMDA current. The indirect action of seletracetam against zinc and [beta]-carboline inhibition of GABA-gated current is absent or very weak but is in contrast to a potent ability to reverse the inhibitory effect of these negative allosteric modulators on glycine-gated currents. The latter may contribute significantly to the mechanism of action of seletracetam. (Supported by UCB, Belgium.)