Chemoenzymatic Synthesis and Pharmacological Characterization of Functionalized Aspartate Analogues As Novel Excitatory Amino Acid Transporter Inhibitors

Aspartate (Asp) derivatives are privileged
compounds for investigating
the roles governed by excitatory amino acid transporters (EAATs) in
glutamatergic neurotransmission. Here, we report the synthesis of
various Asp derivatives with (cyclo)­alkyloxy and (hetero)­aryloxy substituents
at C-3. Their pharmacological properties were characterized at the
EAAT1–4 subtypes. The l-threo-3-substituted
Asp derivatives 13a–e and 13g–k were nonsubstrate inhibitors, exhibiting pan
activity at EAAT1–4 with IC50 values ranging from
0.49 to 15 μM. Comparisons between (dl-threo)-19a–c and (dl-erythro)-19a–c Asp analogues
confirmed that the threo configuration is crucial
for the EAAT1–4 inhibitory activities. Analogues (3b–e) of l-TFB-TBOA (3a)
were shown to be potent EAAT1–4 inhibitors, with IC50 values ranging from 5 to 530 nM. Hybridization of the nonselective
EAAT inhibitor l-TBOA with EAAT2-selective inhibitor WAY-213613
or EAAT3-preferring inhibitor NBI-59159 yielded compounds 8 and 9, respectively, which were nonselective EAAT inhibitors
displaying considerably lower IC50 values at EAAT1–4
(11–140 nM) than those displayed by the respective parent molecules.