The Anticonvulsant MK-801 is a Potent N-methyl-D-aspartate Antagonist

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 83; no. 18; pp. 7104 - 7108
• Main Authors: Erik H. F. Wong, Kemp, John A., Priestley, Tony, Knight, Antony R., Woodruff, Geoffrey N., Iversen, Leslie L.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.09.1986; National Acad Sciences
• Subjects: Animals; Anticonvulsants; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Aspartic Acid - analogs & derivatives; Aspartic Acid - antagonists & inhibitors; Binding Sites; Biological and medical sciences; Brain; Brain - metabolism; Dibenzocycloheptenes - metabolism; Dibenzocycloheptenes - pharmacology; Dizocilpine Maleate; Enantiomers; Excitatory amino acids; Hippocampus; In Vitro Techniques; Ketamine - pharmacology; Ligands; Male; Medical sciences; N-Methylaspartate; Neuropharmacology; Pharmacology; Pharmacology. Drug treatments; Phenazocine - analogs & derivatives; Phenazocine - pharmacology; Phencyclidine - pharmacology; Quisqualic acid; Rats; Rats, Inbred Strains; Receptors; Rat; Rodentia; Oral administration; Brain (Vertebrata); Anticonvulsant; Binding site; Central depressant; Vertebrata; Mammalia; Animal; Opiate receptor σ; Plasma membrane; Mechanism of action
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.83.18.7104

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 σ -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-Asp but not to kainate or quisqualate. The potencies of phencyclidine, ketamine, SKF 10,047, and the enantiomers of MK-801 as N-Me-D-Asp antagonists correlated closely (r = 0.99) with their potencies as inhibitors of [3H]MK-801 binding. This suggests that the MK-801 binding sites are associated with N-Me-D-Asp receptors and provides an explanation for the mechanism of action of MK-801 as an anticonvulsant.