NMethyl Daspartate NMDA receptor antagonists

Memantine 6 is an orally active, noncompetitive NMDA receptor antagonist approved for treatment of moderate-to-severe AD. Memantine also has efficacy in mild-to-moderate AD and is pending labeling approval in the US.

The NMDA receptor plays a key role in long-term potentiation, a process underlying memory and learning consolidation. Pathological activation of NMDA receptors via excess glutamate and calcium drives excitotoxicity associated with AD. A limitation in targeting this receptor is that compounds interacting at the glutamate or glycine sites on this receptor, e.g., phencyclidine (PCP), are known psychomimetics.

Memantine binds weakly to the ion channel-binding site on the NMDA receptor when it is in an open state and thus blocks the tonic pathological activation, induced by micromolar glutamate concentrations. It also normalizes NMDA receptor activation in AD patients, allowing physiological responses to occur, preventing excitotoxic events.32 In nine randomized, double-blind, placebo-controlled clinical trials in dementia and AD patients over a 12-year period, memantine showed improvement in at least one, if not multiple, primary endpoints (1992-2004).

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