The novel anticonvulsant MK‐801 binds to the activated state of the N‐methyl‐d‐aspartate receptor in rat brain

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Abstract
1 The influence of endogenous and exogenous acidic amino acids on the binding of [3H]-MK-801, a selective, non-competitive antagonist of N-methyl-d-aspartate (NMDA) receptors, has been investigated in rat cerebral cortex crude synaptic membranes (CSM). 2 Removal of endogenous glutamate and aspartate from CSM by repeated washing reduced the affinity of [3H]-MK-801 for its binding site (with no change in the total number of binding sites) and increased NMDA-sensitive l-[3H]-glutamate binding. 3 In washed CSM, competitive NMDA antagonists of the dl-α-amino-ω-phosphonocarboxylate series reduced [3H]-MK-801 binding and NMDA-sensitive L-[3H]-glutamate binding, the most active compounds being 2-amino-5-phosphonovalerate (AP5) and 2-amino-7-phosphono-heptanoate (AP7). 4 Exogenous excitatory amino acid agonists enhanced the binding of [3H]-MK-801 to washed CSM by up to 700%. A selective involvement of NMDA receptors in these effects was indicated by the excellent correlation between EC50s for stimulation of [3H]-MK-801 binding and IC50s for inhibition of NMDA-sensitive l-[3H]-glutamate binding in the same membranes. 5 The selective, competitive NMDA receptor antagonist D-AP5 blocked the l-glutamate-induced increase in [3H]-MK-801 binding in a competitive manner with a pA2 value of 6.0. 6 These results seem to reflect a molecular interaction between two distinct components of the NMDA receptor complex: the transmitter recognition site and the site through which MK-801 exerts its antagonist effects, possibly the ion channel.