title: The novel anticonvulsant MK-801 binds to the activated state of the N-methyl-D-aspartate receptor in rat brain.
abstract: 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). 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. In washed CSM, competitive NMDA antagonists of the DL-alpha-amino-omega-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). 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. 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. 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.
mesh_terms: D015763:2-Amino-5-phosphonovalerate; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D001921:Brain / Q000378:metabolism*; D003986:Dibenzocycloheptenes / Q000378:metabolism*; D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D066298:In Vitro Techniques; D016202:N-Methylaspartate; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D013570:Synaptic Membranes / Q000378:metabolism*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D000927:Anticonvulsants; D003986:Dibenzocycloheptenes; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D001224:Aspartic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D014633:Valine