Structural Basis for Understanding Structure−Activity Relationships for the Glutamate Binding Site of the NMDA Receptor

2002 ◽  
Vol 45 (18) ◽  
pp. 3836-3843 ◽  
Author(s):  
Irina G. Tikhonova ◽  
Igor I. Baskin ◽  
Vladimir A. Palyulin ◽  
Nikolai S. Zefirov ◽  
Sergey O. Bachurin
Keyword(s):  
Nmda Receptor ◽  
Binding Site ◽  
Structural Basis ◽  
Structure Activity Relationships ◽  
Glutamate Binding ◽  
Structure Activity

scholarly journals Structural Basis for Understanding Structure−Activity Relationships for the Glutamate Binding Site of the NMDA Receptor.

2002 ◽  
Vol 45 (25) ◽  
pp. 5608-5608 ◽  
Author(s):  
Irina G. Tikhonova ◽  
Igor I. Baskin ◽  
Vladimir A. Palyulin ◽  
Nikolai S. Zefirov ◽  
Sergey O. Bachurin
Keyword(s):  
Nmda Receptor ◽  
Binding Site ◽  
Structural Basis ◽  
Structure Activity Relationships ◽  
Glutamate Binding ◽  
Structure Activity

scholarly journals Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

2017 ◽  
Vol 114 (33) ◽  
pp. E6942-E6951 ◽  
Author(s):  
Genevieve E. Lind ◽  
Tung-Chung Mou ◽  
Lucia Tamborini ◽  
Martin G. Pomper ◽  
Carlo De Micheli ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Binding Affinity ◽  
Binding Mode ◽  
Structural Basis ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Glutamate Binding ◽  
Subunit Interface ◽  
The Central Nervous System ◽  
Contact Residues

NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A–D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with bound ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity.

scholarly journals Modification of the Glutamate Binding Site of the NMDA Receptor During Graded Hypoxia in the Cerebral Cortex of Newborn Piglets. † 183

1997 ◽  
Vol 41 ◽  
pp. 33-33
Author(s):  
Karen I. Fritz ◽  
Joanna Kubin ◽  
Eric Lombardini ◽  
Om P. Mishra ◽  
Maria Delivoria-Papadopoulos
Keyword(s):  
Cerebral Cortex ◽  
Nmda Receptor ◽  
Binding Site ◽  
Newborn Piglets ◽  
Glutamate Binding

6-(1H-Imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione (YM90K) and Related Compounds:  Structure−Activity Relationships for the AMPA-Type Non-NMDA Receptor

1997 ◽  
Vol 40 (5) ◽  
pp. 826-826
Author(s):  
Junya Ohmori ◽  
Shuichi Sakamoto ◽  
Hirokazu Kubota ◽  
Masao Shimizu-Sasamata ◽  
Masamichi Okada ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Related Compounds
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