2. Academic Validation
  3. Synthesis and Structure-Activity Relationships for Glutamate Transporter Allosteric Modulators

Synthesis and Structure-Activity Relationships for Glutamate Transporter Allosteric Modulators

  • J Med Chem. 2024 Apr 25;67(8):6119-6143. doi: 10.1021/acs.jmedchem.3c01909.
Andréia C K Fontana 1,  Adi N R Poli 2,  Jitendra Gour 2,  Yellamelli V V Srikanth 2,  Nicholas Anastasi 2,  Devipriya Ashok 2,  Apeksha Khatiwada 1,  Katelyn L Reeb 1,  Mary Hongying Cheng 3,  Ivet Bahar 4 3,  Scott M Rawls 5,  Joseph M Salvino 2 6
Affiliations

Affiliations

  • 1 Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States.
  • 2 Medicinal Chemistry, Molecular and Cellular Oncogenesis (MCO) Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, United States.
  • 3 Laufer Center for Physical & Quantitative Biology, Stony Brook University, Stony Brook, New York 11794, United States.
  • 4 Department of Biochemistry and Cell Biology, College of Arts & Sciences and School of Medicine, Stony Brook University, Stony Brook, New York 11794, United States.
  • 5 Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140United States.
  • 6 The Wistar Cancer Center Molecular Screening, The Wistar Institute, Philadelphia, Pennsylvania 19104, United States.
PMID: 38626917 DOI: 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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