Stereoselective chemoenzymatic synthesis of the four stereoisomers of l-2-(2-carboxycyclobutyl)glycine and pharmacological characterization at human excitatory amino acid transporter subtypes 1, 2, and 3

TY - JOUR

T1 - Stereoselective chemoenzymatic synthesis of the four stereoisomers of l-2-(2-carboxycyclobutyl)glycine and pharmacological characterization at human excitatory amino acid transporter subtypes 1, 2, and 3

AU - Faure, Sophie

AU - Jensen, Anders A.

AU - Maurat, Vincent

AU - Gu, Xin

AU - Sagot, Emmanuelle

AU - Aitken, David J

AU - Bolte, Jean

AU - Gefflaut, Thierry

AU - Bunch, Lennart

PY - 2006

Y1 - 2006

N2 - The four stereoisomers of l-2-(2-carboxycyclobutyl)glycine, l-CBG-I, l-CBG-II, l-CBG-III, and l-CBG-IV, were synthesized in good yield and high enantiomeric excess, from the corresponding cis and trans-2-oxalylcyclobutanecarboxylic acids 5 and 6 using the enzymes aspartate aminotransferase (AAT) and branched chain aminotransferase (BCAT) from Escherichia coli. The four stereoisomeric compounds were evaluated as potential ligands for the human excitatory amino acid transporters, subtypes 1, 2, and 3 (EAAT1, EAAT2, and EAAT3) in the FLIPR membrane potential assay. While the one trans-stereoisomer, l-CBG-I, displayed weak substrate activity at all three transporters, EAAT1-3, we found a particular pharmacological profile for the other trans-stereoisomer, l-CBG-II, which displayed EAAT1 substrate activity and inhibitory activity at EAAT2 and EAAT3. Whereas l-CBG-III was found to be a weak inhibitor at all three EAAT subtypes, the other cis-stereoisomer l-CBG-IV was a moderately potent inhibitor with 20-30-fold preference for EAAT2/3 over EAAT1.

AB - The four stereoisomers of l-2-(2-carboxycyclobutyl)glycine, l-CBG-I, l-CBG-II, l-CBG-III, and l-CBG-IV, were synthesized in good yield and high enantiomeric excess, from the corresponding cis and trans-2-oxalylcyclobutanecarboxylic acids 5 and 6 using the enzymes aspartate aminotransferase (AAT) and branched chain aminotransferase (BCAT) from Escherichia coli. The four stereoisomeric compounds were evaluated as potential ligands for the human excitatory amino acid transporters, subtypes 1, 2, and 3 (EAAT1, EAAT2, and EAAT3) in the FLIPR membrane potential assay. While the one trans-stereoisomer, l-CBG-I, displayed weak substrate activity at all three transporters, EAAT1-3, we found a particular pharmacological profile for the other trans-stereoisomer, l-CBG-II, which displayed EAAT1 substrate activity and inhibitory activity at EAAT2 and EAAT3. Whereas l-CBG-III was found to be a weak inhibitor at all three EAAT subtypes, the other cis-stereoisomer l-CBG-IV was a moderately potent inhibitor with 20-30-fold preference for EAAT2/3 over EAAT1.

KW - Catalysis

KW - Chemistry, Physical

KW - Cyclobutanes

KW - Excitatory Amino Acid Transporter 1

KW - Excitatory Amino Acid Transporter 3

KW - Glutamate Plasma Membrane Transport Proteins

KW - Glutamates

KW - Glycine

KW - Humans

KW - Indicators and Reagents

KW - Models, Molecular

KW - Molecular Conformation

KW - Physicochemical Phenomena

KW - Stereoisomerism

KW - Structure-Activity Relationship

U2 - 10.1021/jm060822s

DO - 10.1021/jm060822s

M3 - Journal article

C2 - 17064071

SN - 0022-2623

VL - 49

SP - 6532

EP - 6538

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 22

ER -