Anticonvulsant dicarboxyphenylglycines differentially modulate excitatory amino acid release in the rat cerebral cortex.
The 3,4-dicarboxyphenylglycines (3,4-DCPGs) have recently been shown to be effective new anticonvulsant agents in a rodent model of epilepsy, with the racemic mixture showing significantly greater potency than either isomer alone. The (R)-isomer has been identified as a competitive AMPA-type ionotropic glutamate receptor antagonist, whilst (S)-3,4-DCPG is a highly potent and selective metabotropic glutamate receptor 8 (mGlu8 receptor) agonist. We now report the inhibitory activity of (R)- and (RS)-3,4-DCPG, but not (S)-3,4-DCPG, against both 35 mM and 50 mM KCl-evoked glutamate release in the rat cerebral cortex in vitro. In contrast to the anticonvulsant actions of the 3,4-DCPGs, no evidence was obtained for a synergistic inhibitory interaction between the separate isomers. We conclude that whilst inhibition of cortical excitatory amino acid release may contribute to the anticonvulsant actions of (RS)-3,4-DCPG, it does not represent the sole mechanism of action. Synergistic interactions between ligands acting at different subtypes of ionotropic and metabotropic glutamate receptors remains a promising new strategy for the treatment of currently drug-refractory seizure states.
Lee
J J
JJ
Department of Neuroinflammation, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK.
Jane
D E
DE
Croucher
M J
MJ
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001224:Aspartic Acid / Q000032:analysis / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018846:Excitatory Amino Acids / Q000032:analysis / Q000378:metabolism*; D018698:Glutamic Acid / Q000032:analysis / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D011189:Potassium Chloride / Q000494:pharmacology; D020033:Protein Isoforms / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium / Q000378:metabolism
C110733:3,4-dicarboxyphenylglycine; D000927:Anticonvulsants; D001565:Benzoates; D018846:Excitatory Amino Acids; D020033:Protein Isoforms; D014316:Tritium; D001224:Aspartic Acid; D018698:Glutamic Acid; D011189:Potassium Chloride; D005998:Glycine