Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition

Nat Neurosci. 1998 Dec;1(8):659-67. doi: 10.1038/3661.


The phenylethanolamines, ifenprodil and CP-101,606, are NMDA receptor antagonists with promising neuroprotective properties. In recombinant NMDA receptors expressed in Xenopus oocytes, we found that these drugs inhibit NMDA receptors through a unique mechanism, making the receptor more sensitive to inhibition by protons, an endogenous negative modulator. These findings support a critical role for the proton sensor in gating the NMDA receptor and point the way to identifying a context-dependent NMDA receptor antagonist that is inactive at physiological pH, but is a potent inhibitor during the acidic conditions that arise during epilepsy, ischemia and brain trauma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Female
  • Hydrogen-Ion Concentration
  • Neuroprotective Agents / pharmacology*
  • Oocytes / metabolism
  • Piperidines / pharmacology*
  • Protons
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Recombinant Proteins
  • Xenopus laevis


  • Excitatory Amino Acid Antagonists
  • Neuroprotective Agents
  • Piperidines
  • Protons
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Proteins
  • traxoprodil mesylate
  • ifenprodil