Stereoselective Chemoenzymatic Synthesis of the Four Stereoisomers of L-2-(2-Carboxycyclobutyl)glycine and Pharmacological Characterization at Human Excitatory Amino Acid Transp

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• 作者：Sophie Faure ; Anders A. Jensen ; Vincent Maurat ; Xin Gu ; Emmanuelle Sagot ; David J. Aitken ; Jean Bolte ; Thierry Gefflaut ; Lennart Bunch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：November 2, 2006
• 年：2006
• 卷：49
• 期：22
• 页码：6532 - 6538
• 全文大小：223K
• 年卷期：v.49,no.22(November 2, 2006)
• ISSN：1520-4804

文摘

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) andbranched chain aminotransferase (BCAT) from Escherichia coli. The four stereoisomeric compounds wereevaluated 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 pharmacologicalprofile for the other trans-stereoisomer, L-CBG-II, which displayed EAAT1 substrate activity and inhibitoryactivity at EAAT2 and EAAT3. Whereas L-CBG-III was found to be a weak inhibitor at all three EAATsubtypes, the other cis-stereoisomer L-CBG-IV was a moderately potent inhibitor with 20-30-fold preferencefor EAAT2/3 over EAAT1.