Studies of the roles of NMDA and AMPA glutamate receptors in the mechanism of corasole convulsions in mice.

Experiments on mice were performed to study the ability of monocationic and dicationic adamantane and phenylcyclohexyl derivatives to prevent convulsive syndrome induced by i.p. corasole (pentylenetetrazole; 80 mg/kg). Monocationic phenylcyclohexyl derivatives, which are selective blockers of NMDA glutamate receptor channels, along with memantine and MK-801, effectively prevented the appearance of the clonic and tonic components of convulsions at micromolar concentrations. Their dicationic analogs, which block both NMDA and AMPA receptor channels, were ineffective against clonic convulsions, but prevented corasole-induced tonic convulsions at much lower concentrations. The convulsive action of corasole, whose primary target is weakening of the inhibitory action of GABA, appears to be mediated by glutamatergic synaptic transmission. NMDA receptors have a much greater involvement than AMPA receptors in the genesis of clonic convulsions, while AMPA receptor activation appears to be an important component of tonic convulsions.

Comparison of the anticonvulsive activities of organic mono- and dications with their abilities to inhibit NMDA and AMPA glutamate receptors.

The abilities of mono- and dicationic adamantane and phenylcyclohexyl derivatives to (a) block open NMDA and AMPA glutamate receptors in isolated rat brain neurons and (b) prevent convulsions induced in mice by intraventricular NMDA or kainate were studied. Monocations inhibited NMDA receptors in vitro and produced corresponding protection against NMDA-induced convulsions in vivo, but lacked the ability to block AMPA receptors or prevent kainate-induced convulsions. Dications (IEM-1754 and IEM-1925), which inhibited both NMDA and AMPA receptors, were highly effective at protecting against kainate convulsions and were more effective than the corresponding monocations in preventing NMDA convulsions. The origin of convulsions induced by NMDA appears to be based on a component mediated by activation of AMPA receptors. The anticonvulsive activity of IEM-1754 and IEM-1925 were comparable with those of the known NMDA receptor blockers memantine and MK-801. This was combined with an almost complete absence of the side effects characteristic of memantine and MK-801. The complete correspondence between the in vitro data and in vivo results seen with some of the study compounds is evidently associated with their pharmacokinetic properties.

The ability of new non-competitive glutamate receptor blockers to weaken motor disorders in animals.

The ability of mono- and dicationic phenylcyclohexyl derivatives, which are non-competitive glutamate antagonists, to prevent convulsions induced in mice by intragastric NMDA or kainate, to weaken catalepsy induced in rats by haloperidol and to exert their own influences of movement activity and behavior in animals was studied. The actions of study compounds were compared with those of the known NMDA antagonists memantine and dizocilpine. NMDA-induced convulsions were effectively prevented by both mono- and dications, while only dications were effective against kainate convulsions. Anticataleptic activity was significantly more marked in monocations, which lacked the ability to block non-NMDA receptors. Side effects on motor coordination were less marked with study compounds than with dizocilpine. Thus, the effects of phenylcyclohexyl derivatives in in vivo experimental models correlate with their anti-NMDA and anti-AMPA activity. They can be regarded as potential agents for treating parkinsonism and other motor disorders.