Amantadine inhibits NMDA receptors by accelerating channel closure during channel block

J Neurosci. 2005 Mar 30;25(13):3312-22. doi: 10.1523/JNEUROSCI.4262-04.2005.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amantadine / pharmacology*
  • Analgesics, Non-Narcotic / pharmacology*
  • Animals
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Electric Stimulation / methods
  • Embryo, Mammalian
  • Glycine / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Ion Channel Gating / drug effects*
  • Ion Channels / drug effects
  • Ion Channels / physiology*
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology
  • Neurons / drug effects*
  • Patch-Clamp Techniques / methods
  • Rats
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Time Factors
  • Transfection / methods


  • Analgesics, Non-Narcotic
  • Ion Channels
  • NR1A NMDA receptor, rat
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Amantadine
  • Glycine