Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition

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