Synthesis and Structure-Activity Relationships for Glutamate Transporter Allosteric Modulators
Fontana, Andréia C. K. Poli, Adi N. R. Gour, Jitendra Srikanth, Yellamelli V. V. Anastasi, Nicholas Ashok, Devipriya Khatiwada, Apeksha Reeb, Katelyn L. Hongying Cheng, Mary Bahar, Ivet
Fontana, Andréia C. K.
Poli, Adi N. R.
Gour, Jitendra
Srikanth, Yellamelli V. V.
Anastasi, Nicholas
Ashok, Devipriya
Khatiwada, Apeksha
Reeb, Katelyn L.
Hongying Cheng, Mary
Bahar, Ivet
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2024-04-16
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https://doi.org/10.1021/acs.jmedchem.3c01909
Abstract
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.
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Journal of Medicinal Chemistry, Vol. 67, Iss. 8
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