Context-dependent GluN2B-selective inhibitors of NMDA receptor function are neuroprotective with minimal side effects.
Stroke remains a significant problem despite decades of work on neuroprotective strategies. NMDA receptor (NMDAR) antagonists are neuroprotective in preclinical models, but have been clinically unsuccessful, in part due to side effects. Here we describe a prototypical GluN2B-selective antagonist with an IC50 value that is 10-fold more potent at acidic pH 6.9 associated with ischemic tissue compared to pH 7.6, a value close to the pH in healthy brain tissue. This should maximize neuroprotection in ischemic tissue while minimizing on-target side effects associated with NMDAR blockade in noninjured brain regions. We have determined the mechanism underlying pH-dependent inhibition and demonstrate the utility of this approach in vivo. We also identify dicarboxylate dimers as a novel proton sensor in proteins. These results provide insight into the molecular basis of pH-dependent neuroprotective NMDAR block, which could be beneficial in a wide range of neurological insults associated with tissue acidification.
Department of Pharmacology, Emory University, Atlanta, GA 30322 USA.
Hongjie
H
Yuan
Department of Pharmacology, Emory University, Atlanta, GA 30322 USA.
Scott J
SJ
Myers
Department of Chemistry, Emory University, Atlanta, GA 30322 USA.
Gordon
G
Wells
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298 USA.|Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA 23298 USA.
Katherine L
KL
Nicholson
Department of Pharmacology, Emory University, Atlanta, GA 30322 USA.
Sharon A
SA
Swanger
Department of Pharmacology, Emory University, Atlanta, GA 30322 USA.
Polina
P
Lyuboslavsky
Department of Chemistry, Emory University, Atlanta, GA 30322 USA.
Yesim A
YA
Tahirovic
Department of Chemistry, Emory University, Atlanta, GA 30322 USA.
David S
DS
Menaldino
Department of Pharmacology, Emory University, Atlanta, GA 30322 USA.
Thota
T
Ganesh
Department of Chemistry, Emory University, Atlanta, GA 30322 USA.
Lawrence J
LJ
Wilson
Department of Chemistry, Emory University, Atlanta, GA 30322 USA.
Dennis C
DC
Liotta
Department of Chemistry, Emory University, Atlanta, GA 30322 USA.
James P
JP
Snyder
Department of Pharmacology, Emory University, Atlanta, GA 30322 USA.
Stephen F
SF
Traynelis
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000633:toxicity; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism
C121001:NR2B NMDA receptor; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate