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.
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.
Faure
Sophie
S
Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Jensen
Anders A
AA
Maurat
Vincent
V
Gu
Xin
X
Sagot
Emmanuelle
E
Aitken
David J
DJ
Bolte
Jean
J
Gefflaut
Thierry
T
Bunch
Lennart
L
D002384:Catalysis; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D027341:Excitatory Amino Acid Transporter 1 / Q000187:drug effects*; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3 / Q000187:drug effects*; D050491:Glutamate Plasma Membrane Transport Proteins / Q000187:drug effects*; D005971:Glutamates / Q000138:chemical synthesis; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C515234:2-(2-carboxycyclobutyl)glycine; D003503:Cyclobutanes; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D005971:Glutamates; D007202:Indicators and Reagents; C493400:SLC1A1 protein, human; C493397:SLC1A2 protein, human; C493394:SLC1A3 protein, human; D005998:Glycine