Synergy between retigabine and GABA in modulating the convulsant site of the GABAA receptor complex

The molecular mechanism underlying the activity of the novel antiepileptic drug retigabine is not yet fully understood. The aim of this study was to investigate whether retigabine interacts directly with the GABA(A) receptor complex (gamma-aminobutyric acid). Receptor-binding assays were conducted using rat brain membranes. [H-3]-t-Butyl-bicyclo-orthobenzoate ([H-3]TBOB) was used as a tracer ligand. We determined the effects of GABA and retigabine in the presence of several concentrations of GABA on the binding of [H-3]TBOB. GABA inhibited [H-3]TBOB binding with an EC50 of 4.8 muM. In the absence of GABA, retigabine inhibited [H-3]TBOB with an EC50 of 124 muM and an EC50 of 42 muM in the presence of 2.5 muM GABA. Isobolic analysis revealed that retigabine acts in synergy with GABA in displacing [H-3]TBOB. This synergy could be quantified by a molecular model in which GABA and retigabine both allosterically displace [H-3]TBOB, and retigabine allosterically enhances the binding of GABA and vice versa with a factor of 4. In summary, we found that retigabine does indeed interact with a site on the GABA(A) receptor complex, and this site is positively allosterically coupled with the GABA site. This GABA-positive effect may well contribute to the clinical anticonvulsive effects of retigabine. (C) 2003 Elsevier Science B.V. All rights reserved.