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

FEBS Letters

Nadler, Varda¹  Kloog, Yoel¹  Sokolovsky, Mordechai¹ 

[1] Department of Biochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel

关键词: Phencyclidine;    NMDA receptor;    Dibenzocycloalkenimine;    PCP;    phencyclidine;    TCP;    N-[1-(2-thienyl)cyclohexyl]piperidine;    NMDA;    N-methyl-D-aspartate;    AP-5;    D-(−)2-amino-5-phosphovaleric acid;    MK-801;    (+)-5-methyl-10;    11-dihydro-5H-dibenzo[a;    d]cyclohepten-5;    10-imine maleate;   

DOI  :  10.1016/0014-5793(88)80664-1

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown