Amantadine inhibits NMDA receptors by accelerating channel closure and stabilizing closed states, which may explain its distinct clinical utility compared to other channel blockers.
May inform mechanistic studies of amantadine in neurological disease; leaves open translation to human efficacy or dosing.
The channel of NMDA receptors is blocked by a wide variety of drugs. NMDA receptor channel blockers include drugs of abuse that induce psychotic behavior, such as phencyclidine, and drugs with wide therapeutic utility, such as amantadine and memantine. We describe here the molecular mechanism of amantadine inhibition. In contrast to most other described channel-blocking molecules, amantadine causes the channel gate of NMDA receptors to close more quickly. Our results confirm that amantadine binding inhibits current flow through NMDA receptor channels but show that its main inhibitory action at pharmaceutically relevant concentrations results from stabilization of closed states of the channel. The surprising variation in the clinical utility of NMDA channel blockers may in part derive from their diverse effects on channel gating.
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Blanpied et al. (2005) studied this question.
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