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.
Wlaź
P
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Department of Pharmacology, Faculty of Veterinary Medicine, Agricultural University, Lublin, Poland. wlaz@ursus.ar.lublin.pl
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D000963:Antimetabolites / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001667:Binding, Competitive / Q000502:physiology; D001923:Brain Chemistry / Q000502:physiology; D003523:Cycloserine / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004597:Electroshock; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D009498:Neurotoxins / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D018009:Receptors, Glycine / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D000927:Anticonvulsants; D000963:Antimetabolites; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D009498:Neurotoxins; D015363:Quinolones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D003523:Cycloserine; C094635:L 701324