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

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 β-indolyloxy Asp analogs - with the aim to probe a hitherto unexplored adjacent pocket to the substrate binding site. The pharmacological properties of - were characterized at hEAAT1-3 and rEAAT4 in a conventional [H]-d-Asp uptake assay. Notably, thiophene analog and the -trifluoromethyl phenyl analog were found to be hEAAT1,2-preferring inhibitors exhibiting IC values in the high nanomolar range (0.21-0.71 μM) at these two transporters versus IC values in the low micromolar range at EAAT3,4 (1.6-8.9 μM). In summary, the results presented herein open up for further structure-activity relationship studies of this new scaffold.