PMID- 26919761
OWN - NLM
STAT- MEDLINE
DCOM- 20160823
LR  - 20181202
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 59
IP  - 6
DP  - 2016 Mar 24
TI  - Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators 
      (PAMs): Tuning Deactivation Kinetics via Structure-Based Design.
PG  - 2760-79
LID - 10.1021/acs.jmedchem.5b02010 [doi]
AB  - The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable 
      ionotropic glutamate receptor that is activated by the coagonists glycine and 
      glutamate. NMDARs are critical to synaptic signaling and plasticity, and their 
      dysfunction has been implicated in a number of neurological disorders, including 
      schizophrenia, depression, and Alzheimer's disease. Herein we describe the 
      discovery of potent GluN2A-selective NMDAR positive allosteric modulators (PAMs) 
      starting from a high-throughput screening hit. Using structure-based design, we 
      sought to increase potency at the GluN2A subtype, while improving selectivity 
      against related alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors 
      (AMPARs). The structure-activity relationship of channel deactivation kinetics 
      was studied using a combination of electrophysiology and protein crystallography. 
      Effective incorporation of these strategies resulted in the discovery of GNE-0723 
      (46), a highly potent and brain penetrant GluN2A-selective NMDAR PAM suitable for 
      in vivo characterization.
FAU - Volgraf, Matthew
AU  - Volgraf M
FAU - Sellers, Benjamin D
AU  - Sellers BD
FAU - Jiang, Yu
AU  - Jiang Y
AD  - Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
FAU - Wu, Guosheng
AU  - Wu G
AD  - Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
FAU - Ly, Cuong Q
AU  - Ly CQ
FAU - Villemure, Elisia
AU  - Villemure E
FAU - Pastor, Richard M
AU  - Pastor RM
FAU - Yuen, Po-wai
AU  - Yuen PW
AD  - Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
FAU - Lu, Aijun
AU  - Lu A
AD  - Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
FAU - Luo, Xifeng
AU  - Luo X
AD  - Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
FAU - Liu, Mingcui
AU  - Liu M
AD  - Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
FAU - Zhang, Shun
AU  - Zhang S
AD  - Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
FAU - Sun, Liang
AU  - Sun L
AD  - Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
FAU - Fu, Yuhong
AU  - Fu Y
AD  - Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
FAU - Lupardus, Patrick J
AU  - Lupardus PJ
FAU - Wallweber, Heidi J A
AU  - Wallweber HJ
FAU - Liederer, Bianca M
AU  - Liederer BM
FAU - Deshmukh, Gauri
AU  - Deshmukh G
FAU - Plise, Emile
AU  - Plise E
FAU - Tay, Suzanne
AU  - Tay S
FAU - Reynen, Paul
AU  - Reynen P
FAU - Herrington, James
AU  - Herrington J
FAU - Gustafson, Amy
AU  - Gustafson A
FAU - Liu, Yichin
AU  - Liu Y
FAU - Dirksen, Akim
AU  - Dirksen A
AD  - Ion Channels Group, Evotec AG ; Manfred Eigen Campus, Essener Bogen 7, 22419 
      Hamburg, Germany.
FAU - Dietz, Matthias G A
AU  - Dietz MG
AD  - Ion Channels Group, Evotec AG ; Manfred Eigen Campus, Essener Bogen 7, 22419 
      Hamburg, Germany.
FAU - Liu, Yanzhou
AU  - Liu Y
FAU - Wang, Tzu-Ming
AU  - Wang TM
FAU - Hanson, Jesse E
AU  - Hanson JE
FAU - Hackos, David
AU  - Hackos D
FAU - Scearce-Levie, Kimberly
AU  - Scearce-Levie K
FAU - Schwarz, Jacob B
AU  - Schwarz JB
LA  - eng
PT  - Journal Article
DEP - 20160308
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (Receptors, AMPA)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - SY7Q814VUP (Calcium)
RN  - VH92ICR8HX (N-methyl D-aspartate receptor subtype 2A)
SB  - IM
MH  - Animals
MH  - CHO Cells
MH  - Calcium/metabolism
MH  - Cricetinae
MH  - Cricetulus
MH  - Crystallography, X-Ray
MH  - Drug Discovery
MH  - Excitatory Amino Acid Antagonists/*chemical synthesis/*pharmacology
MH  - HEK293 Cells
MH  - High-Throughput Screening Assays
MH  - Humans
MH  - Kinetics
MH  - Models, Molecular
MH  - Patch-Clamp Techniques
MH  - Receptors, AMPA/drug effects
MH  - Receptors, N-Methyl-D-Aspartate/*drug effects
MH  - Structure-Activity Relationship
EDAT- 2016/02/28 06:00
MHDA- 2016/08/24 06:00
CRDT- 2016/02/28 06:00
PHST- 2016/02/28 06:00 [entrez]
PHST- 2016/02/28 06:00 [pubmed]
PHST- 2016/08/24 06:00 [medline]
AID - 10.1021/acs.jmedchem.5b02010 [doi]
PST - ppublish
SO  - J Med Chem. 2016 Mar 24;59(6):2760-79. doi: 10.1021/acs.jmedchem.5b02010. Epub 
      2016 Mar 8.