Kynurenate and 2-amino-5-phosphonovalerate interact with multiple binding sites of the N-methyl-D-aspartate-sensitive glutamate receptor domain.

By studying the binding of [3H]glycine and [3H]glutamate to rat synaptic membranes in the presence of 2-amino-5-phosphonovalerate (APV) and kynurenate (KYN) we have demonstrated that KYN is more potent than APV in displacing [3H]glycine, while an opposite order of potency was seen in displacing [3H]glutamate. Moreover, 2-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) inhibited only [3H]glutamate binding. The [3H]MK-801 specific binding was inhibited by all of the above antagonists; this action was abolished by glutamate, while glycine partially reversed only the action of KYN. Hence, KYN inhibits glutamate receptors by preferentially interfering with glycine recognition sites, while APV preferentially interacts with N-methyl-D-aspartate (NMDA) recognition sites.