Anti-convulsant and adverse effects of the glycineB receptor ligands, D-cycloserine and L-701,324: comparison with competitive and non-competitive N-methyl-D-aspartate receptor antagonists.

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.