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

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Abstract
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°C are slow processes, both of which follow first order kinetics (t ⋍70 and 180 min, respectively). Both reactions are markedly accelerated by glutamate and glycine (t ⋍2‐8 and 4 min, respectively), which allow bimolecular association kinetics of the labeled drug with the receptors whereas equilibrium binding of [3H]MK‐801 (K d 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.