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

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

SN - 0022-2623

VL - 48

SP - 7980

EP - 7992

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 25

ER -