title: The novel anticonvulsant MK-801: a potent and specific ligand of the brain phencyclidine/sigma-receptor.
abstract: MK-801 (5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate) is a novel anticonvulsant agent reported to antagonize certain N-methyl-D-aspartate (NMDA)-mediated effects non-competitively. The question arises of the mechanism underlying the anti-NMDA and anticonvulsant effects of MK-801. In the present study MK-801 is shown to be an extremely potent inhibitor of the binding of N-[3H] (1-[2-thienyl]cyclohexyl)piperidine ([3H]TCP) to brain phencyclidine (PCP)/sigma-receptors. Its IC50 value of 3.8 +/- 0.8 nM in this assay ranks it as the most potent known ligand of brain PCP/sigma-receptors. Addition of MK-801 altered the apparent Kd but not the apparent Bmax values for [3H]TCP binding, indicating a competitive interaction. The specificity of action of MK-801 is supported by the finding that MK-801 strongly inhibited the binding of (+)-N-[3H]allylnormetazocine ((+)-[3H]SKF 10,047) to the PCP/sigma-receptor but its effect on (+)-[3H]SKF 10,047 binding to the non-PCP, haloperidol-sensitive sigma-binding site was weaker by several orders of magnitude. Furthermore, MK-801 exerts PCP-like antagonistic effects upon NMDA-induced [3H]norepinephrine release. These findings support the concept that the anticonvulsant and anti-NMDA effects of MK-801 result from its being the most potent known ligand of PCP/sigma-receptors.
authors.affiliation: Department of Psychiatry, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461.
authors.forename: R
authors.initials: R
authors.lastname: Sircar
authors.forename: M
authors.initials: M
authors.lastname: Rappaport
authors.forename: R
authors.initials: R
authors.lastname: Nichtenhauser
authors.forename: S R
authors.initials: SR
authors.lastname: Zukin
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D003986:Dibenzocycloheptenes / Q000378:metabolism / Q000494:pharmacology*; D016291:Dizocilpine Maleate; D007700:Kinetics; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma
chemical_list: D000927:Anticonvulsants; D003986:Dibenzocycloheptenes; D017981:Receptors, Neurotransmitter; D011957:Receptors, Opioid; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; D016291:Dizocilpine Maleate