Synthesis and Structure–Activity Relationships for Glutamate Transporter Allosteric Modulators

Excitatory amino acid transporters (EAATs) are essential
CNS proteins
that regulate glutamate levels. Excess glutamate release and alteration
in EAAT expression are associated with several CNS disorders. Previously,
we identified positive allosteric modulators (PAM) of EAAT2, the main
CNS transporter, and have demonstrated their neuroprotective properties in vitro. Herein, we report on the structure–activity
relationships (SAR) for the analogs identified from virtual screening
and from our medicinal chemistry campaign. This work identified several
selective EAAT2 positive allosteric modulators (PAMs) such as compounds 4 (DA-023) and 40 (NA-014) from a library of
analogs inspired by GT949, an early generation compound. This series
also provides nonselective EAAT PAMs, EAAT inhibitors, and inactive
compounds that may be useful for elucidating the mechanism of EAAT
allosteric modulation.