2010
DOI: 10.1002/chem.201001366
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Partial Agonists and Subunit Selectivity at NMDA Receptors

Abstract: Subunit-selective ligands for glutamate receptors remains an area of interest as glutamate is the major excitatory neurotransmitter in the brain and involved in a number of diseased states in the central nervous system (CNS). Few subtype-selective ligands are known, especially among the N-methyl-D-aspartic acid (NMDA) receptor class. Development of these ligands seems to be a difficult task because of the conserved region in the binding site of the NMDA receptor subunits. A few scaffolds have been developed sh… Show more

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Cited by 8 publications
(12 citation statements)
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References 29 publications
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“…Since Et-NHP5G is a partial agonist on both GluN2A and GluN2D, we speculate that formation of Van der Waal interaction between the propyl group and GluN2A Val685 or GluN2D Val710 work toward antagonism, whereas weaker Van der Waal interaction may increase agonist efficacy. This idea is consistent with a previous study, showing that relative agonist efficacy is reduced when the extent of steric clash (i.e., Van der Waal interaction) between agonists and the residue at this position in GluN2B (Val686) is increased (Hansen et al, 2005) [see also Risgaard et al (2010)]. Furthermore, substitutions on the glutamate backbone [e.g., (2S,4R)-4-methyl glutamate (SYM2081)] that favor GluN1/GluN2D activation are predicted from docking studies to be directed into this same general vicinity within the GluN2 binding pocket .…”
Section: Glun1/glun2asupporting
confidence: 93%
See 1 more Smart Citation
“…Since Et-NHP5G is a partial agonist on both GluN2A and GluN2D, we speculate that formation of Van der Waal interaction between the propyl group and GluN2A Val685 or GluN2D Val710 work toward antagonism, whereas weaker Van der Waal interaction may increase agonist efficacy. This idea is consistent with a previous study, showing that relative agonist efficacy is reduced when the extent of steric clash (i.e., Van der Waal interaction) between agonists and the residue at this position in GluN2B (Val686) is increased (Hansen et al, 2005) [see also Risgaard et al (2010)]. Furthermore, substitutions on the glutamate backbone [e.g., (2S,4R)-4-methyl glutamate (SYM2081)] that favor GluN1/GluN2D activation are predicted from docking studies to be directed into this same general vicinity within the GluN2 binding pocket .…”
Section: Glun1/glun2asupporting
confidence: 93%
“…Partial agonists that show subunit selectivity can be used to identify specific structural elements that influence activation of receptor subtypes. The NHP5G series of agonists represents a particularly useful set of compounds with which to probe questions about activation of NMDA receptors because these agonists possess an unusually wide range of efficacies across different NMDA receptor subunits (Hansen et al, 2005;Clausen et al, 2008) [see also Risgaard et al (2010)]. Ethyl-and propylsubstituted NHP5G (i.e., Et-NHP5G and Pr-NHP5G, respectively) interact with the glutamate binding site in the GluN2 NMDA receptor subunit (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…The key agonist contact residues are conserved almost universally across the glutamate receptor family and strongly conserved within the glutamate binding pocket across GluN2 subunits [4749], although the hinge region in the GluN2 ligand binding domain shows agonist-dependent diversity [50]. Whereas the glutamate binding pockets show some differences [51] that can be exploited to develop agonists with limited preference for different GluN2 subunits [52], in general, the highly conserved nature of the agonist binding domain diminishes the prospect that strong subunit selectivity can be achieved through conventional modifications of competitive antagonist structure.…”
Section: Competitive Antagonists and Channel Blockersmentioning
confidence: 99%
“…31 This segregation within the CeA may account for the reported involvement of CeA in antinociception and nociception. 55 The differential selectivity of AP5 and NMDA for NMDA receptor subtypes (NR2A–D) 57,63 may also contribute the antinociceptive actions these treatments. For example, differential expression of NMDA receptor subtypes on CeA neurons that are involved in the expression or suppression of pain affect may contribute to the different mechanisms whereby both AP5 and NMDA inhibit pain-induced vocalizations.…”
Section: Discussionmentioning
confidence: 99%