Antagonists at the ionotropic non-NMDA [AMPA (amino-methyl proprionic acid)/kainate] type of glutamate receptors have been suggested to possess several advantages compared to NMDA (N-methyl-D-aspartate) receptor antagonists, particularly in terms of risk/benefit ratio, but the non-NMDA receptor antagonists available so far have not fulfilled this promise. From a large series of pyrrolyl-quinoxalinedione derivatives, we selected six new competitive non-NMDA receptor antagonists. The basis of selection was high potency and selectivity for AMPA and/or kainate receptors, high in vivo potency after systemic administration, and an acceptable ratio between neuroprotective or anticonvulsant effects and adverse effects. Pharmacological characteristics of these novel compounds are described in this study with special emphasis on their effects in the kindling model of temporal lobe epilepsy, the most common type of epilepsy in humans. In most experiments, NBQX and the major antiepileptic drug valproate were used for comparison with the novel compounds. The novel non-NMDA receptor antagonists markedly differed in their AMPA and kainate receptor affinities from NBQX. Thus, while NBQX essentially did not bind to kainate receptors at relevant concentrations, several of the novel compounds exhibited affinity to rat brain kainate receptors or recombinant kainate receptor subtypes in addition to AMPA receptors. One compound, LU 97175, bound to native high affinity kainate receptors and rat GluR5-GluR7 subunits, i.e. low affinity kainate binding sites, with much higher affinities than to AMPA receptors. All compounds potently blocked AMPA-induced 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 receptors and low affinity kainate receptor subunits were potent anticonvulsants in the kindling model, whereas the AMPA receptor-selective LU 112313 was the least selective compound in this model, indicating that non-NMDA antagonists 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 action.
The synthesis and pharmacological activity of new (E),(Z)-[6-(alkylamino)-11H-dibenz[b,e]azepin-11- ylidene]acetonitriles 12-45 and (E),(Z)-[6-(aminoalkoxy)-11H-dibenz[b,e]azepin-11-ylidene] acetonitriles 46-51 are described. The introduction of the cyanomethylene group into the 11-position of the 11H-dibenz[b,e]azepine framework has been carried out by a Wittig-Horner reaction under mild conditions. The (E),(Z) isomers were separated by fractional crystallization, assignment being achieved by X-ray analysis. A number of (E),(Z)-[6-(alkylamino)-11H-dibenz-[b,e]azepin-11-ylidene] acetonitriles (12, 14, 16, 20) show potent neuroleptic activity (2-7 times that of clozapine) in animal tests. The screening included tests for sedative and anticholinergic activity in mice, apomorphine and tryptamine antagonism in rats, and muscle-relaxing activity in rabbits. The divergence in the activity profile in the case of the separated (E),(Z) isomers has been observed as an interesting new aspect: the (Z) isomers show a significantly higher sedative and muscle-relaxant activity, whereas the (E) isomers possess a higher anticholinergic efficacy and somewhat greater apomorphine antagonism. Broad changes in the basic side chain were made in order to investigate structure-activity relationships. The important geometrical parameters for the molecules, obtained by X-ray analysis, were compared with the corresponding features in dopamine agonists and antagonists.
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