Discovery of (R)-2-amino-3-triazolpropanoic acid derivatives as NMDA receptor glycine site agonists with GluN2 subunit-specific activity
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Discovery of (R)-2-amino-3-triazolpropanoic acid derivatives as NMDA receptor glycine site agonists with GluN2 subunit-specific activity. / Zhao, Fabao; Mazis, Georgios; Yi, Feng; Lotti, James S.; Layeux, Michael S.; Schultz, Eric P.; Bunch, Lennart; Hansen, Kasper B.; Clausen, Rasmus P.
In: Frontiers in Chemistry, Vol. 10, 1008233, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Discovery of (R)-2-amino-3-triazolpropanoic acid derivatives as NMDA receptor glycine site agonists with GluN2 subunit-specific activity
AU - Zhao, Fabao
AU - Mazis, Georgios
AU - Yi, Feng
AU - Lotti, James S.
AU - Layeux, Michael S.
AU - Schultz, Eric P.
AU - Bunch, Lennart
AU - Hansen, Kasper B.
AU - Clausen, Rasmus P.
N1 - Funding Information: The authors acknowledge financial support from the National Institutes of Health [NS097536, GM140963] to KH and a Summer Fellowship to ML. from the Center for Structural and Functional Neuroscience at the University of Montana. FZ acknowledge financial support from the National Natural Science Foundation of China [82204200], the China Scholarship Council, the International Postdoctoral Exchange Fellowship Program (Talent-Introduction Program) [YJ20210,279], the China Postdoctoral Science Foundation [2022M711939], and the Natural Science Foundation of Shandong Province [ZR2022QH287 and ZR2022QH312]. Funding Information: We would like to acknowledge Alexandria University, Alexandria, Egypt, and King Abdullah University of Science and Technology, Saudi Arabia, for supporting the research.
PY - 2022
Y1 - 2022
N2 - N-Methyl-d-aspartate (NMDA) receptors play critical roles in central nervous system function and are involved in variety of brain disorders. We previously developed a series of (R)-3-(5-furanyl)carboxamido-2-aminopropanoic acid glycine site agonists with pronounced variation in activity among NMDA receptor GluN1/2A-D subtypes. Here, a series of (R)-2-amino-3-triazolpropanoic acid analogues with a novel chemical scaffold is designed and their pharmacological properties are evaluated at NMDA receptor subtypes. We found that the triazole can function as a bioisostere for amide to produce glycine site agonists with variation in activity among NMDA receptor subtypes. Compounds 13g and 13i are full and partial agonists, respectively, at GluN1/2C and GluN1/2D with 3- to 7-fold preference in agonist potency for GluN1/2C-D over GluN1/2A-B subtypes. The agonist binding mode of these triazole analogues and the mechanisms by which the triazole ring can serve as a bioisostere for amide were further explored using molecular dynamics simulations. Thus, the novel (R)-2-amino-3-triazolpropanoic acid derivatives reveal insights to agonist binding at the GluN1 subunit of NMDA receptors and provide new opportunities for the design of glycine site agonists.
AB - N-Methyl-d-aspartate (NMDA) receptors play critical roles in central nervous system function and are involved in variety of brain disorders. We previously developed a series of (R)-3-(5-furanyl)carboxamido-2-aminopropanoic acid glycine site agonists with pronounced variation in activity among NMDA receptor GluN1/2A-D subtypes. Here, a series of (R)-2-amino-3-triazolpropanoic acid analogues with a novel chemical scaffold is designed and their pharmacological properties are evaluated at NMDA receptor subtypes. We found that the triazole can function as a bioisostere for amide to produce glycine site agonists with variation in activity among NMDA receptor subtypes. Compounds 13g and 13i are full and partial agonists, respectively, at GluN1/2C and GluN1/2D with 3- to 7-fold preference in agonist potency for GluN1/2C-D over GluN1/2A-B subtypes. The agonist binding mode of these triazole analogues and the mechanisms by which the triazole ring can serve as a bioisostere for amide were further explored using molecular dynamics simulations. Thus, the novel (R)-2-amino-3-triazolpropanoic acid derivatives reveal insights to agonist binding at the GluN1 subunit of NMDA receptors and provide new opportunities for the design of glycine site agonists.
KW - co-agonist
KW - ionotropic glutamate receptors
KW - ligand-gated ion channel
KW - subtype selectivity
KW - two-electrode voltage-clamp electrophysiology
U2 - 10.3389/fchem.2022.1008233
DO - 10.3389/fchem.2022.1008233
M3 - Journal article
C2 - 36465862
AN - SCOPUS:85143205785
VL - 10
JO - Frontiers in Chemistry
JF - Frontiers in Chemistry
SN - 2296-2646
M1 - 1008233
ER -
ID: 329206993