TY - JOUR

T1 - β-Indolyloxy Functionalized Aspartate Analogs as Inhibitors of the Excitatory Amino Acid Transporters (EAATs)

AU - Liu, Na

AU - Jensen, Anders A.

AU - Bunch, Lennart

PY - 2020

Y1 - 2020

N2 - The excitatory amino acid transporters (EAATs) mediate uptake of the major excitatory neurotransmitter L-glutamate (Glu). The essential functions governed by these transporters in regulating the central Glu level make them interesting therapeutic targets in a wide range of neurodegenerative and psychiatric disorders. L-Aspartate (Asp), another EAAT substrate, has served as a privileged scaffold for the development of EAAT inhibitors. In this study, we designed and synthesized the first beta-indolyloxy Asp analogs 15a-d with the aim to probe a hitherto unexplored adjacent pocket to the substrate binding site. The pharmacological properties of 15a-d were characterized at hEAAT1-3 and rEAAT4 in a conventional [H-3]-D-Asp uptake assay. Notably, thiophene analog 15b and the Para-trifluoromethyl phenyl analog 15d were found to be hEAAT1,2-preferring inhibitors exhibiting IC50 values in the high nanomolar range (0.21-0.71 mu M) at these two transporters versus IC50 values in the low micromolar range at EAAT3,4 (1.6-8.9 mu M). In summary, the results presented herein open up for further structure-activity relationship studies of this new scaffold.

AB - The excitatory amino acid transporters (EAATs) mediate uptake of the major excitatory neurotransmitter L-glutamate (Glu). The essential functions governed by these transporters in regulating the central Glu level make them interesting therapeutic targets in a wide range of neurodegenerative and psychiatric disorders. L-Aspartate (Asp), another EAAT substrate, has served as a privileged scaffold for the development of EAAT inhibitors. In this study, we designed and synthesized the first beta-indolyloxy Asp analogs 15a-d with the aim to probe a hitherto unexplored adjacent pocket to the substrate binding site. The pharmacological properties of 15a-d were characterized at hEAAT1-3 and rEAAT4 in a conventional [H-3]-D-Asp uptake assay. Notably, thiophene analog 15b and the Para-trifluoromethyl phenyl analog 15d were found to be hEAAT1,2-preferring inhibitors exhibiting IC50 values in the high nanomolar range (0.21-0.71 mu M) at these two transporters versus IC50 values in the low micromolar range at EAAT3,4 (1.6-8.9 mu M). In summary, the results presented herein open up for further structure-activity relationship studies of this new scaffold.

KW - EAAT inhibitors

KW - TBOA analogs

KW - aspartate analogs

KW - glutamate transporters

U2 - 10.1021/acsmedchemlett.0c00342

DO - 10.1021/acsmedchemlett.0c00342

M3 - Journal article

C2 - 33214831

VL - 11

SP - 2212

EP - 2220

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 11

ER -