Synthesis and Structure-Activity Relationships for Glutamate Transporter Allosteric Modulators

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Apr 16

PMID 38626917

Authors

Andreia C K Fontana

Adi N R Poli

Jitendra Gour

Yellamelli V V Srikanth

Nicholas Anastasi

Devipriya Ashok

Apeksha Khatiwada

Katelyn L Reeb

Mary Hongying Cheng

Ivet Bahar

Scott M Rawls

Joseph M Salvino

Affiliations

Soon will be listed here.

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 . 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 (DA-023) and (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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