The novel anticonvulsant MK-801: a potent and specific ligand of the brain phencyclidine/gd-receptor

Ratna Sircar, Michael Rappaport, Roxanne Nichtenhauser, Stephan R. Zukin

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70 Scopus citations


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-spd-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]cyclohexy)piperidine) ([s3H]TCP to brain phencyclidine (PCP)/δ-receptors. It is IC5) value of 3.8 ± 0.8 nM in this assay ranks it as the most potent known ligand of brain PCP/δ-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/δ-receptor but its effect on (+)-[3H]SKF 10.047 binding to the non-PCP, haloperidol-sensitive δ-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/δ-receptors.

Original languageEnglish (US)
Pages (from-to)235-240
Number of pages6
JournalBrain Research
Issue number1-2
StatePublished - Dec 1 1987
Externally publishedYes


  • (+)-[H]SKF 10,047 competition
  • Anticonvulsant
  • Haloperidol-sensitive non-PCP/δ-binding site
  • MK-801
  • N-Methyl-d-aspartate (NMDA)-stimulated [H]norepinephrine release
  • Phencyclidine (PCP)/δ-receptor
  • [H]TCP binding

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology
  • Clinical Neurology
  • General Neuroscience


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