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.

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