Anticonvulsant dicarboxyphenylglycines differentially modulate excitatory amino acid release in the rat cerebral...

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.