Mode of binding of [3H]dibenzocycloalkenimine (MK-801) to the N-methyl-D-aspartate (NMDA) receptor and its therapeutic implication.

Binding of the labeled anticonvulsant drug [3H]dibenzocycloalkenimine [(3H]MK-801 to the N-methyl-D-aspartate (NMDA) receptor and its dissociation from the receptor at 25 degrees C are slow processes, both of which follow first order kinetics (t1/2 approximately equal to 70 and 180 min, respectively). Both reactions are markedly accelerated by glutamate and glycine (t1/2 approximately equal to 5-8 and 4 min, respectively), which allow bimolecular association kinetics of the labeled drug with the receptors whereas equilibrium binding of [3H]MK-801 (Kd 2-4 nM) is hardly affected by glutamate and glycine. The data suggest that MK-801 acts as a steric blocker of the NMDA receptor channel. The competitive antagonist D-(-)-2-amino-5-phosphovaleric acid (AP-5) freezes the receptor in a state which precludes either binding of [3H]MK-801 to the receptor channel or its dissociation from it. These findings have therapeutic implications.