TY - JOUR
T1 - Design, synthesis and pharmacological characterization of coumarin-based fluorescent analogs of excitatory amino acid transporter subtype 1 selective inhibitors, UCPH-101 and UCPH-102
AU - Huynh, Tri Hien Viet
AU - Abrahamsen, Bjarke
AU - Madsen, Karsten Kirkegaard
AU - Gonzalez-Franquesa, Alba
AU - Jensen, Anders A.
AU - Bunch, Lennart
PY - 2012/12/1
Y1 - 2012/12/1
N2 - The excitatory amino acid transporters (EAATs) play a pivotal role in regulating the synaptic concentration of glutamate in the mammalian central nervous system. To date, five different subtypes have been identified, named EAAT15 in humans (and GLAST, GLT-1, EAAC1, EAAT4, and EAAT5, respectively, in rodents). Recently, we have published and presented a structure-activity relationship (SAR) study of a novel class of selective inhibitors of EAAT1 (and GLAST), with the analogs UCPH-101 (IC50 = 0.66 μM) and UCPH-102 (IC50 = 0.43 μM) being the most potent inhibitors in the series. In this paper, we present the design, synthesis and pharmacological evaluation of six coumarin-based fluorescent analogs of UCPH-101/102 as subtype-selective inhibitors at EAAT1. Analogs 1114 failed to inhibit EAAT1 function (IC 50 values >300 μM), whereas analogs 15 and UCPH-102F inhibited EAAT1 with IC50 values in the medium micromolar range (17 μM and 14 μM, respectively). Under physiological pH no fluorescence was observed for analog 15, while a bright blue fluorescence emission was observed for analog UCPH-102F. Regrettably, under confocal laser scanning microscopy selective visualization of expression of EAAT1 over EAAT3 was not possible due to nonspecific binding of UCPH-102F.
AB - The excitatory amino acid transporters (EAATs) play a pivotal role in regulating the synaptic concentration of glutamate in the mammalian central nervous system. To date, five different subtypes have been identified, named EAAT15 in humans (and GLAST, GLT-1, EAAC1, EAAT4, and EAAT5, respectively, in rodents). Recently, we have published and presented a structure-activity relationship (SAR) study of a novel class of selective inhibitors of EAAT1 (and GLAST), with the analogs UCPH-101 (IC50 = 0.66 μM) and UCPH-102 (IC50 = 0.43 μM) being the most potent inhibitors in the series. In this paper, we present the design, synthesis and pharmacological evaluation of six coumarin-based fluorescent analogs of UCPH-101/102 as subtype-selective inhibitors at EAAT1. Analogs 1114 failed to inhibit EAAT1 function (IC 50 values >300 μM), whereas analogs 15 and UCPH-102F inhibited EAAT1 with IC50 values in the medium micromolar range (17 μM and 14 μM, respectively). Under physiological pH no fluorescence was observed for analog 15, while a bright blue fluorescence emission was observed for analog UCPH-102F. Regrettably, under confocal laser scanning microscopy selective visualization of expression of EAAT1 over EAAT3 was not possible due to nonspecific binding of UCPH-102F.
U2 - 10.1016/j.bmc.2012.09.049
DO - 10.1016/j.bmc.2012.09.049
M3 - Journal article
C2 - 23072958
SN - 0968-0896
VL - 20
SP - 6831
EP - 6839
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
IS - 23
ER -