l-701324 and Epilepsy

In this study, the anticonvulsant and adverse effects of compounds that belong to four different categories of systemically available N-methyl-D-aspartate (NMDA) receptor ligands were compared, namely the competitive antagonist CGP 40116, the noncompetitive antagonist MK-801 (dizocilpine), the glycineB receptor antagonist L-701,324, and the glycineB receptor high-efficacy partial agonist D-cycloserine. The maximal electroshock seizures (MES), which are widely used to detect drug efficacy against generalized tonic-clonic seizures in humans, were produced by transcorneal electrical stimulation. Abolition of tonic hind-limb extension was taken as the end-point. The drug-induced motor and long-term memory deficits were quantified by using the inverted screen test and the step-through passive-avoidance test, respectively. All tested compounds exhibited significant anticonvulsant effect. The rank order of potency for the respective compounds was: MK-801 = CGP 40116 > L-701,324 >> D-cycloserine. All of these compounds induced motor impairment at doses close to those found to be anticonvulsant, however, hyperlocomotion and stereotyped behavior occurred only with MK-801. The highest protective indices [PI = TD50 (inverted screen)/ED50 (MES)] were calculated for CGP 40116 and D-cycloserine (2.4 and 2.2, respectively). When tested for memory impairment at one-half the MES ED50, again only MK-801 induced significant memory disruption in the passive avoidance test. In conclusion, these results suggest that glycineB receptor high-efficacy partial agonists and competitive NMDA receptor antagonists may be advantageous to noncompetitive NMDA antagonists and glycineB receptor antagonists as potential antiepileptic drugs.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Antimetabolites; Avoidance Learning; Binding, Competitive; Brain Chemistry; Cycloserine; Dizocilpine Maleate; Electroshock; Epilepsy; Excitatory Amino Acid Antagonists; Ligands; Male; Mice; Neurotoxins; Quinolones; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate

The aim of this study was to assess whether a drug which combines an antagonistic action at both NMDA and non-NMDA receptors offers advantages for treatment of epileptic seizures compared to drugs which antagonize only one of these ionotropic glutamate receptors. The novel glutamate receptor antagonist LU 73068 (4,5-dihydro-1-methyl-4-oxo-7-trifluoromethylimidazo[1,2a]quinoxal ine-2-carbonic acid) binds with high affinity to both the glycine site of the NMDA receptor (Ki 185 nM) and to the AMPA receptor (Ki 158 nM). Furthermore, binding experiments with recombinant kainate receptor subunits showed that LU 73068 binds to several of these subunits, particularly to rGluR7 (Ki 104 nM) and rGluR5 (Ki 271 nM). In comparison, the prototype non-NMDA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline) binds with high affinity to AMPA receptors only. Both NBQX and LU 73068 were about equieffective after i.p. injection in mice to block lethal convulsions induced by AMPA or NMDA. In the rat amygdala kindling model of temporal lobe epilepsy, LU 73068 dose-dependently increased the focal seizure threshold (afterdischarge threshold, ADT). When rats were stimulated with a current 20% above the individual control ADT, LU 73068 completely blocked seizures with an ED50 of 4.9 mg kg(-1). Up to 20 mg kg(-1), only moderate adverse effects, e.g. slight ataxia, were observed. NBQX, 10 mg kg(-1), and the glycine/NMDA site antagonist L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-quinoline-2(1H)one), 2.5 or 5 mg kg(-1), exerted no anticonvulsant effects in kindled rats when administered alone, but combined treatment with both drugs resulted in a significant ADT increase. The data indicate that combination of glycine/NMDA and non-NMDA receptor antagonism in a single drug is an effective means of developing a potent and effective anticonvulsant agent.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants; Disease Models, Animal; Dizocilpine Maleate; Drug Synergism; Epilepsy; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Imidazoles; Kindling, Neurologic; Male; Mice; Mice, Inbred Strains; N-Methylaspartate; Quinolones; Quinoxalines; Receptors, AMPA; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Tritium