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.
D015763:2-Amino-5-phosphonovalerate; D000818:Animals; D000927:Anticonvulsants; D003986:Dibenzocycloheptenes / Q000378:metabolism*; D016291:Dizocilpine Maleate; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D005998:Glycine / Q000494:pharmacology; D007700:Kinetics; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D000927:Anticonvulsants; D003986:Dibenzocycloheptenes; D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D014633:Valine; D005998:Glycine