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

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 K_d but not the apparent B_max 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.