Chemoenzymatic synthesis of a series of 4-substituted glutamate analogues and pharmacological characterization at human glutamate transporters subtypes 1-3

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Chemoenzymatic synthesis of a series of 4-substituted glutamate analogues and pharmacological characterization at human glutamate transporters subtypes 1-3. / Alaux, Sebastien; Kusk, Mie; Sagot, Emanuelle; Bolte, Jean; Jensen, Anders A.; Bräuner-Osborne, Hans; Gefflaut, Thierry; Bunch, Lennart.

In: Journal of Medicinal Chemistry, Vol. 48, No. 25, 2005, p. 7980-92.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Alaux, S, Kusk, M, Sagot, E, Bolte, J, Jensen, AA, Bräuner-Osborne, H, Gefflaut, T & Bunch, L 2005, 'Chemoenzymatic synthesis of a series of 4-substituted glutamate analogues and pharmacological characterization at human glutamate transporters subtypes 1-3', Journal of Medicinal Chemistry, vol. 48, no. 25, pp. 7980-92. https://doi.org/10.1021/jm050597z

APA

Alaux, S., Kusk, M., Sagot, E., Bolte, J., Jensen, A. A., Bräuner-Osborne, H., Gefflaut, T., & Bunch, L. (2005). Chemoenzymatic synthesis of a series of 4-substituted glutamate analogues and pharmacological characterization at human glutamate transporters subtypes 1-3. Journal of Medicinal Chemistry, 48(25), 7980-92. https://doi.org/10.1021/jm050597z

Vancouver

Alaux S, Kusk M, Sagot E, Bolte J, Jensen AA, Bräuner-Osborne H et al. Chemoenzymatic synthesis of a series of 4-substituted glutamate analogues and pharmacological characterization at human glutamate transporters subtypes 1-3. Journal of Medicinal Chemistry. 2005;48(25):7980-92. https://doi.org/10.1021/jm050597z

Author

Alaux, Sebastien ; Kusk, Mie ; Sagot, Emanuelle ; Bolte, Jean ; Jensen, Anders A. ; Bräuner-Osborne, Hans ; Gefflaut, Thierry ; Bunch, Lennart. / Chemoenzymatic synthesis of a series of 4-substituted glutamate analogues and pharmacological characterization at human glutamate transporters subtypes 1-3. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 25. pp. 7980-92.

Bibtex

@article{2bd47cead0294c498f97460d76fa0ee8,
title = "Chemoenzymatic synthesis of a series of 4-substituted glutamate analogues and pharmacological characterization at human glutamate transporters subtypes 1-3",
abstract = "A series of nine L-2,4-syn-4-alkylglutamic acid analogues (1a-i) were synthesized in high yield and high enantiomeric excess (>99% ee) from their corresponding 4-substituted ketoglutaric acids (2a-i), using the enzyme aspartate aminotransferase (AAT) from pig heart or E. coli. The synthesized compounds were evaluated as potential ligands for the glutamate transporters EAAT1, EAAT2, and EAAT3 (excitatory amino acid transporter, subtypes 1-3) in the FLIPR membrane potential (FMP) assay. We found a distinct change in the pharmacological profile when the 4-methyl group (compound 1a, an EAAT1 substrate and EAAT2,3 inhibitor) was extended to a 4-ethyl group, compound 1b, as this analogue is an inhibitor at all three subtypes, EAAT1-3. Furthermore, we conclude that both large and bulky hydrophobic substituents in the 4-position of L-2,4-syn Glu are allowed by all three glutamate transporter subtypes EAAT1-3 while maintaining inhibitory activity.",
keywords = "Animals, Aspartate Aminotransferases, Cell Line, Excitatory Amino Acid Transporter 2, Excitatory Amino Acid Transporter 3, Glutamates, Humans, Ketoglutaric Acids, Membrane Potentials, Models, Molecular, Myocardium, Stereoisomerism, Structure-Activity Relationship, Swine",
author = "Sebastien Alaux and Mie Kusk and Emanuelle Sagot and Jean Bolte and Jensen, {Anders A.} and Hans Br{\"a}uner-Osborne and Thierry Gefflaut and Lennart Bunch",
year = "2005",
doi = "10.1021/jm050597z",
language = "English",
volume = "48",
pages = "7980--92",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "25",

}

RIS

TY - JOUR

T1 - Chemoenzymatic synthesis of a series of 4-substituted glutamate analogues and pharmacological characterization at human glutamate transporters subtypes 1-3

AU - Alaux, Sebastien

AU - Kusk, Mie

AU - Sagot, Emanuelle

AU - Bolte, Jean

AU - Jensen, Anders A.

AU - Bräuner-Osborne, Hans

AU - Gefflaut, Thierry

AU - Bunch, Lennart

PY - 2005

Y1 - 2005

N2 - A series of nine L-2,4-syn-4-alkylglutamic acid analogues (1a-i) were synthesized in high yield and high enantiomeric excess (>99% ee) from their corresponding 4-substituted ketoglutaric acids (2a-i), using the enzyme aspartate aminotransferase (AAT) from pig heart or E. coli. The synthesized compounds were evaluated as potential ligands for the glutamate transporters EAAT1, EAAT2, and EAAT3 (excitatory amino acid transporter, subtypes 1-3) in the FLIPR membrane potential (FMP) assay. We found a distinct change in the pharmacological profile when the 4-methyl group (compound 1a, an EAAT1 substrate and EAAT2,3 inhibitor) was extended to a 4-ethyl group, compound 1b, as this analogue is an inhibitor at all three subtypes, EAAT1-3. Furthermore, we conclude that both large and bulky hydrophobic substituents in the 4-position of L-2,4-syn Glu are allowed by all three glutamate transporter subtypes EAAT1-3 while maintaining inhibitory activity.

AB - A series of nine L-2,4-syn-4-alkylglutamic acid analogues (1a-i) were synthesized in high yield and high enantiomeric excess (>99% ee) from their corresponding 4-substituted ketoglutaric acids (2a-i), using the enzyme aspartate aminotransferase (AAT) from pig heart or E. coli. The synthesized compounds were evaluated as potential ligands for the glutamate transporters EAAT1, EAAT2, and EAAT3 (excitatory amino acid transporter, subtypes 1-3) in the FLIPR membrane potential (FMP) assay. We found a distinct change in the pharmacological profile when the 4-methyl group (compound 1a, an EAAT1 substrate and EAAT2,3 inhibitor) was extended to a 4-ethyl group, compound 1b, as this analogue is an inhibitor at all three subtypes, EAAT1-3. Furthermore, we conclude that both large and bulky hydrophobic substituents in the 4-position of L-2,4-syn Glu are allowed by all three glutamate transporter subtypes EAAT1-3 while maintaining inhibitory activity.

KW - Animals

KW - Aspartate Aminotransferases

KW - Cell Line

KW - Excitatory Amino Acid Transporter 2

KW - Excitatory Amino Acid Transporter 3

KW - Glutamates

KW - Humans

KW - Ketoglutaric Acids

KW - Membrane Potentials

KW - Models, Molecular

KW - Myocardium

KW - Stereoisomerism

KW - Structure-Activity Relationship

KW - Swine

U2 - 10.1021/jm050597z

DO - 10.1021/jm050597z

M3 - Journal article

C2 - 16335922

VL - 48

SP - 7980

EP - 7992

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 25

ER -

ID: 38484762