The excitotoxicity of heterocyclic dicarboxylic acids in rat hippocampal slices: structure-activity relationships

The structural resemblance of certain heterocyclic dicarboxylates to aspartate and glutamate led investigators to study their potency as agonists and antagonists of the N-methyl-D-aspartate (NMDA) receptor. The sensitivity of hypoxic rat hippocampal slices to NMDA ligands is several fold greater than that of normoxic slices. In the present study, the excitotoxic potency of heterocyclic dicarboxylates was assessed electrophysiologically by measuring their ability to enhance hypoxic and hypoglycemic neuronal damage in the rat hippocampal slice preparation. Four compounds were tested: quinolinate (QUIN), 4,5-imidazole-dicarboxylate (IZDA), 1,2,3-triazole-4,5-dicarboxylate (TZDA), and 2,3-pyrazinedicarboxylate (PZDA). QUIN was the most toxic drug in enhancing both hypoxic and hypoglycemic neuronal damage. IZDA and TZDA were slightly less toxic than QUIN, while PZDA was innocuous. The effect of the 3 active drugs was blocked by the NMDA competitive antagonist DL-2-amino-5-phosphonovalerate. The sequence -N-CH(COOH)-CH(COOH)- appears to be a prerequisite for a heterocyclic dicarboxylate to exert NMDA-type agonistic properties. A 5-membered ring heterocyclic compound which contains more than one nitrogen atom in its ring retains its NMDA-type toxicity while a 6-membered ring with more than one nitrogen atom (PZDA) does not.