Structure-activity 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-chromene-3-carbonitrile (UCPH-101) and absolute configurational assignment using infrared and vibrational circular dichroism spectroscopy in combination with ab initio hartree-fock calculations

Tri H. V. Huynh, Irene Shim, Henrik Bohr, Bjarke Abrahamsen, Birgitte Nielsen, Anders A. Jensen, Lennart Bunch

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    Abstract

    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 EAAT1-5 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 (IC(50) value 20 µM), whereas analogues 8 and 10 were inactive (IC(50) values >100 µM). 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-Fock calculations. Analogues 11a (RS-isomer) and 12b (RR-isomer) inhibited EAAT1 (IC(50) values 5.5 and 3.8 µM, respectively), whereas analogues 11b (SS-isomer) and 12a (SR-isomer) failed to inhibit EAAT1 uptake (IC(50) values >300 µM).
    Original languageEnglish
    JournalJournal of Medicinal Chemistry
    Volume55
    Issue number11
    Pages (from-to)5403-12
    Number of pages10
    ISSN0022-2623
    DOIs
    Publication statusPublished - 2012

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