β‑Sulfonamido Functionalized Aspartate Analogues as Excitatory Amino Acid Transporter Inhibitors: Distinct Subtype Selectivity Profiles Arising from Subtle Structural Differences

In this study inspired
by previous work on 3-substituted Asp analogues,
we designed and synthesized a total of 32 β-sulfonamide Asp
analogues and characterized their pharmacological properties at the
excitatory amino acid transporter subtypes EAAT1, EAAT2, and EAAT3.
In addition to several potent EAAT inhibitors displaying IC50 values ∼1 μM at all three subtypes, this elaborate
structure–activity relationship also identified analogues exhibiting
distinct preferences or selectivities for specific transporter subtypes.
Introduction of two fluorine atoms on the phenyl ring yielded analogue 4y that displayed an IC50 of 0.8 μM at EAAT1
with a 14- and 9-fold preference over EAAT2 and EAAT3, respectively.
Conversely, the m-CF3-phenyl analogue 4r was a potent selective EAAT2-inhibitor (IC50 = 2.8 μM) exhibiting 30- and 50-fold selectivity over EAAT1
and EAAT3, respectively. In conclusion, even small structural differences
in these β-sulfonamide Asp analogues provide analogues with
diverse EAAT subtype selectivity profiles.