[3H]MK-801 labels a site on the N-methyl-D-aspartate receptor channel complex in rat brain membranes

J Neurochem. 1988 Jan;50(1):274-81. doi: 10.1111/j.1471-4159.1988.tb13260.x.


The potent noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist [3H]MK-801 bound with nanomolar affinity to rat brain membranes in a reversible, saturable, and stereospecific manner. The affinity of [3H]MK-801 was considerably higher in 5 mM Tris-HCl (pH 7.4) than in previous studies using Krebs-Henseleit buffer. [3H]MK-801 labels a homogeneous population of sites in rat cerebral cortical membranes with KD of 6.3 nM and Bmax of 2.37 pmol/mg of protein. This binding was unevenly distributed among brain regions, with hippocampus greater than cortex greater than olfactory bulb = striatum greater than medulla-pons, and the cerebellum failing to show significant binding. Detailed pharmacological characterization indicated [3H]MK-801 binding to a site which was competitively and potently inhibited by known noncompetitive NMDA receptor antagonists, such as phencyclidine, thienylcyclohexylpiperidine (TCP), ketamine, N-allylnormetazocine (SKF 10,047), cyclazocine, and etoxadrol, a specificity similar to sites labelled by [3H]TCP. These sites were distinct from the high-affinity sites labelled by the sigma receptor ligand (+)-[3H]SKF 10,047. [3H]MK-801 binding was allosterically modulated by the endogenous NMDA receptor antagonist Mg2+ and by other active divalent cations. These data suggest that [3H]MK-801 labels a high-affinity site on the NMDA receptor channel complex, distinct from the NMDA recognition site, which is responsible for the blocking action of MK-801 and other noncompetitive NMDA receptor antagonists.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anticonvulsants
  • Brain / metabolism*
  • Cations, Divalent
  • Cell Membrane / metabolism
  • Cerebral Cortex / metabolism
  • Dibenzocycloheptenes / metabolism*
  • Dizocilpine Maleate
  • Kinetics
  • Male
  • Phenazocine / analogs & derivatives
  • Phenazocine / metabolism
  • Phencyclidine / analogs & derivatives
  • Phencyclidine / metabolism
  • Rats
  • Rats, Inbred Strains
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Neurotransmitter / metabolism*
  • Tissue Distribution
  • Tritium


  • Anticonvulsants
  • Cations, Divalent
  • Dibenzocycloheptenes
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Neurotransmitter
  • Tritium
  • Dizocilpine Maleate
  • SK&F 10047
  • tenocyclidine
  • Phenazocine
  • Phencyclidine