Structure鈥揂ctivity Relationship Study of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chro

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• 作者：Tri H. V. Huynh ; Irene Shim ; Henrik Bohr ; Bjarke Abrahamsen ; Birgitte Nielsen ; Anders A. Jensen ; Lennart Bunch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：55
• 期：11
• 页码：5403-5412
• 全文大小：552K
• 年卷期：v.55,no.11(June 14, 2012)
• ISSN：1520-4804

文摘

The excitatory amino acid transporters (EAATs) play essential roles in regulating the synaptic concentration of the neurotransmitter glutamate in the mammalian central nervous system. To date, five subtypes have been identified, named EAAT1鈥? in humans, and GLAST, GLT-1, EAAC1, EAAT4, and EAAT5 in rodents, respectively. In this paper, we present the design, synthesis, and pharmacological evaluation of seven 7-N-substituted analogues of UCPH-101/102. Analogue 9 inhibited EAAT1 in the micromolar range (IC₅₀ value 20 渭M), whereas analogues 8 and 10 were inactive (IC₅₀ values >100 渭M). The diastereomeric pairs 11a/11b and 12a/12b were separated by HPLC and the absolute configuration assigned by VCD technique in combination with ab initio Hartree鈥揊ock calculations. Analogues 11a (RS-isomer) and 12b (RR-isomer) inhibited EAAT1 (IC₅₀ values 5.5 and 3.8 渭M, respectively), whereas analogues 11b (SS-isomer) and 12a (SR-isomer) failed to inhibit EAAT1 uptake (IC₅₀ values >300 渭M).