ANTICONVULSANT AND ADVERSE-EFFECTS OF THE GLYCINE, RECEPTOR LIGANDS, D-CYCLOSERINE AND L-701,324 - COMPARISON WITH COMPETITIVE AND NONCOMPETITIVE N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS

In this study, the anticonvulsant and adverse effects of compounds tha t belong to four different categories of systemically available N-meth yl-D-aspartate (NMDA) receptor ligands were compared, namely the compe titive antagonist CGP 40116, the noncompetitive antagonist MK-801 (diz ocilpine), the glycine, receptor antagonist L-701,324, and the glycine , receptor high-efficacy partial agonist D-cycloserine, The maximal el ectroshock seizures (MES), which are widely used to detect drug effica cy against generalized tonic-clonic seizures in humans, were produced by transcorneal electrical stimulation. Abolition of tonic hind-limb e xtension was taken as the end-point. The drug-induced motor and long-t erm 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-70 1,324 >> D-cycloserine. All of these compounds induced motor impairmen t at doses close to those found to be anticonvulsant, however, hyperlo comotion and stereotyped behavior occurred only with MK-801, The highe st protective indices [PI = TD50 (inverted screen)/ED50 (MES)] were ca lculated for CGP 40116 and D-cycloserine (2.4 and 2.2, respectively). When tested for memory impairment at one-half the MES ED,,, again only MK-801 induced significant memory disruption in the passive avoidance test. In conclusion, these results suggest that glycine, receptor hig h-efficacy partial agonists and competitive NMDA receptor antagonists may be advantageous to noncompetitive NMDA antagonists and glycine, re ceptor antagonists as potential antiepileptic drugs. (C) 1998 Elsevier Science Inc.