Sep 1, 1986

The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist

Proceedings of the National Academy of Sciences of the United States of America
E H WongL L Iversen

Abstract

The compound MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate)] is a potent anticonvulsant that is active after oral administration and whose mechanism of action is unknown. We have detected high-affinity (Kd = 37.2 +/- 2.7 nM) binding sites for [3H]MK-801 in rat brain membranes. These sites are heat-labile, stereoselective, and regionally specific, with the hippocampus showing the highest density of sites, followed by cerebral cortex, corpus striatum, and medulla-pons. There was no detectable binding in the cerebellum. MK-801 binding sites exhibited a novel pharmacological profile, since none of the major neurotransmitter candidates were active at these sites. The only compounds that were able to compete for [3H]MK-801 binding sites were substances known to block the responses of excitatory amino acids mediated by the N-methyl-D-aspartate (N-Me-D-Asp) receptor subtype. These comprised the dissociative anesthetics phencyclidine and ketamine and the sigma-type opioid N-allylnormetazocine (SKF 10,047). Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-As...Continue Reading

Mentioned in this Paper

Tissue Membrane
Anticonvulsants
Aspartic Acid, Magnesium-Potassium (2:1:2) Salt
Entire Corpus Striatum
Entire Medulla Oblongata
Phencyclidine Hydrobromide
Amino Acids, I.V. solution additive
August Rats
Antagonist Muscle Action
Brain

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