A new pyrrolyl-quinoxalinedione series of non-NMDA glutamate receptor antagonists: pharmacological characterization and comparison with NBQX and valproate in the kindling model of epilepsy

Antagonists at the ionotropic non-NMDA [AMPA (amino-methyl proprionic acid) /kainate] type of glutamate receptors have been suggested to possess severa l advantages compared to NMDA (N-methyl-D-aspartate) receptor antagonists, particularly in terms of risk/benefit ratio, but the non-NMDA receptor anta gonists available so far have not fulfilled this promise. From a large seri es of pyrrolyl-quinoxalinedione derivatives, we selected six new competitiv e non-NMDA receptor antagonists, The basis of selection was high potency an d selectivity for AMPA and/or kainate receptors, high in vivo potency after systemic administration, and an acceptable ratio between neuroprotective o r anticonvulsant effects and adverse effects. Pharmacological characteristi cs of these novel compounds are described in this study with special emphas is on their effects in the kindling model of temporal lobe epilepsy, the mo st common type of epilepsy in humans. In most experiments, NBQX and the maj or antiepileptic drug valproate were used for comparison with the novel com pounds. The novel non-NMDA receptor antagonists markedly differed in their AMPA and kainate receptor affinities from NBQX. Thus, while NBQX essentiall y did not bind to kainate receptors at relevant concentrations, several of the novel compounds exhibited affinity to rat brain kainate receptors or re combinant kainate receptor subtypes in addition to AMPA receptors. One comp ound, LU 97175, bound to native high affinity kainate receptors and rat Glu R5-GluR7 subunits, i.e. low affinity kainate binding sites, with much highe r affinities than to AMPA receptors. All compounds potently blocked AMPA-in duced cell death in vitro and, except LU 97175, AMPA-induced convulsions in vivo. In the kindling model, compounds with a high affinity for GluR7 (LU 97175) or compounds (LU 115455, LU 136541) which potently bind to AMPA rece ptors and low affinity kainate receptor subunits were potent anticonvulsant s in the kindling model, whereas the AMPA receptor-selective LU 112313 was the least selective compound in this model, indicating that non-NMDA antago nists acting at both AMPA and kainate receptors are more effective in this model than AMPA receptor-selective drugs. Three of the novel compounds, i.e . LU 97175, LU 115455 and LU 136541, exerted potent anticonvulsant effects without inducing motor impairment in the rotarod test. This combination of actions is thought to be a prerequisite for selective anticonvulsant drug a ction.