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Nat Neurosci. 1998 Dec;1(8):659-67.

Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition.

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Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.


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.

[Indexed for MEDLINE]

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