Whole‐cell and single‐channel recording techniques have provided a great deal of information about the nature of the N‐methyl‐D‐aspartate (NMDA) receptor channel complex and are beginning to lead to quasimolecular models of drug action. Currently five ligand‐binding domains are known to exist on the NMDA receptor channel complex: 1) an agonist‐binding site for which structural analogues of L‐glutamate have been developed as competitive antagonists; 2) a divalent cation‐binding site within the ion channel pore, at which Mg binds to produce voltage‐dependent channel block; 3) a divalent cation‐binding site near the extracellular face of the membrane, at which Zn and Cd but not Mg bind to produce a voltage‐independent block; 4) an anaesthetic binding site within the pore, at which ketamine, phencyclidine, MK‐801, and desipramine bind with high affinity to produce voltage‐dependent ion channel block of long duration; and 5) a regulatory site on the extracellular face of the membrane at which glycine binds to promote NMDA receptor channel activity. This potentiating action of glycine, to a large extent, reflects a block of fast desensitization, via an increase in the rate constant for return of desensitized NMDA receptors to their resting state. Drugs that competitively displace glycine from its binding site, but that are without glycine‐like activity, act as noncompetitive NMDA receptor antagonists. The combination of these unusual physiological and pharmacological properties seems to have been exploited in the brain to allow the NMDA receptor to gate a variety of complex behaviours, including memory formation, neuronal cell death in stroke and ischemia, and electrical excitability in epilepsy. The existence of multiple ligand‐binding sites on the NMDA receptor complex provides many potential avenues for the development of new classes of centrally active drugs.
Drug Development Research – Wiley
Published: Jan 1, 1989
Keywords: patch clamp; ion channel block; desensitization; allosteric regulation
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