Discovery of (R)-2-amino-3-triazolpropanoic acid derivatives as NMDA receptor glycine site agonists with GluN2 subunit-specific activity

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Standard

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.

I: Frontiers in Chemistry, Bind 10, 1008233, 2022.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Zhao, F, Mazis, G, Yi, F, Lotti, JS, Layeux, MS, Schultz, EP, Bunch, L, Hansen, KB & Clausen, RP 2022, 'Discovery of (R)-2-amino-3-triazolpropanoic acid derivatives as NMDA receptor glycine site agonists with GluN2 subunit-specific activity', Frontiers in Chemistry, bind 10, 1008233. https://doi.org/10.3389/fchem.2022.1008233

APA

Zhao, F., Mazis, G., Yi, F., Lotti, J. S., Layeux, M. S., Schultz, E. P., Bunch, L., Hansen, K. B., & Clausen, R. P. (2022). Discovery of (R)-2-amino-3-triazolpropanoic acid derivatives as NMDA receptor glycine site agonists with GluN2 subunit-specific activity. Frontiers in Chemistry, 10, [1008233]. https://doi.org/10.3389/fchem.2022.1008233

Vancouver

Zhao F, Mazis G, Yi F, Lotti JS, Layeux MS, Schultz EP o.a. Discovery of (R)-2-amino-3-triazolpropanoic acid derivatives as NMDA receptor glycine site agonists with GluN2 subunit-specific activity. Frontiers in Chemistry. 2022;10. 1008233. https://doi.org/10.3389/fchem.2022.1008233

Author

Zhao, Fabao ; Mazis, Georgios ; Yi, Feng ; Lotti, James S. ; Layeux, Michael S. ; Schultz, Eric P. ; Bunch, Lennart ; Hansen, Kasper B. ; Clausen, Rasmus P. / Discovery of (R)-2-amino-3-triazolpropanoic acid derivatives as NMDA receptor glycine site agonists with GluN2 subunit-specific activity. I: Frontiers in Chemistry. 2022 ; Bind 10.

Bibtex

@article{6e827a9799ed4d2d885dac2ef9259f33,
title = "Discovery of (R)-2-amino-3-triazolpropanoic acid derivatives as NMDA receptor glycine site agonists with GluN2 subunit-specific activity",
abstract = "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.",
keywords = "co-agonist, ionotropic glutamate receptors, ligand-gated ion channel, subtype selectivity, two-electrode voltage-clamp electrophysiology",
author = "Fabao Zhao and Georgios Mazis and Feng Yi and Lotti, {James S.} and Layeux, {Michael S.} and Schultz, {Eric P.} and Lennart Bunch and Hansen, {Kasper B.} and Clausen, {Rasmus P.}",
note = "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. ",
year = "2022",
doi = "10.3389/fchem.2022.1008233",
language = "English",
volume = "10",
journal = "Frontiers in Chemistry",
issn = "2296-2646",
publisher = "Frontiers Media S.A.",

}

RIS

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