title: Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition.
abstract: 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.
authors: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. dmott@emory.edu
authors: D D
authors: DD
authors: Mott
authors: J J
authors: JJ
authors: Doherty
authors: S
authors: S
authors: Zhang
authors: M S
authors: MS
authors: Washburn
authors: M J
authors: MJ
authors: Fendley
authors: P
authors: P
authors: Lyuboslavsky
authors: S F
authors: SF
authors: Traynelis
authors: R
authors: R
authors: Dingledine
mesh_terms: D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006863:Hydrogen-Ion Concentration; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011522:Protons; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins; D014982:Xenopus laevis
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D010880:Piperidines; D011522:Protons; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; C095106:traxoprodil mesylate; C010739:ifenprodil