2. Academic Validation
  3. Vesicular Glutamate Transporter Inhibitors: Structurally Modified Brilliant Yellow Analogs

Vesicular Glutamate Transporter Inhibitors: Structurally Modified Brilliant Yellow Analogs

  • Neurochem Res. 2017 Jun;42(6):1823-1832. doi: 10.1007/s11064-017-2198-8.
Jason Kehrl 1 2,  J Christian Althaus 1,  Hollis D Showalter 3 4,  DiAndra M Rudzinski 5,  Michael A Sutton 1 6,  Tetsufumi Ueda 7 8 9
Affiliations

Affiliations

  • 1 Molecular & Behavioral Neuroscience Institute, Medical School, University of Michigan, 109 Zina Pitcher, Ann Arbor, MI, 48109, USA.
  • 2 IMS Consulting Group, 485 Lexington Ave, New York, NY, 10017, USA.
  • 3 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI, 48109, USA. howalh@umich.edu.
  • 4 Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI, 48109, USA. howalh@umich.edu.
  • 5 Cheminpharma LLC, 23 Business Park Drive, Branford, CT, 06405, USA.
  • 6 Department of Molecular and Integrative Physiology, Medical School, University of Michigan, 1150 West Medical Center Dr., Ann Arbor, MI, 48109, USA.
  • 7 Molecular & Behavioral Neuroscience Institute, Medical School, University of Michigan, 109 Zina Pitcher, Ann Arbor, MI, 48109, USA. tueda@med.umich.edu.
  • 8 Department of Pharmacology, Medical School, University of Michigan, 2301 MSRB, 1150 West Medical Center Dr., Ann Arbor, MI, 48109, USA. tueda@med.umich.edu.
  • 9 Department of Psychiatry, Medical School, University of Michigan, 1500 East Medical Center Dr., Ann Arbor, MI, 48104, USA. tueda@med.umich.edu.
PMID: 28255754 DOI: 10.1007/s11064-017-2198-8
Abstract

Glutamate uptake into synaptic vesicles in nerve terminals is a pivotal step in glutamate synaptic transmission. Glutamate is the major excitatory neurotransmitter and, as such, the vesicular glutamate transporter (VGLUT) responsible for this uptake is involved in a variety of nervous system functions and various types of pathophysiology. As yet, no VGLUT-specific, membrane-permeable agents have been developed to affect neuronal function in intact neurons, although two potent VGLUTspecific inhibitors are known. These compounds contain diazo and highly charged sulfonic acid groups, rendering them membrane-impermeable and potentially cytotoxic. In an effort to eliminate these undesirable properties, we have developed two novel agents, Brilliant Yellow analogs 1 and 2, which are free of these two groups. We show here that these agents retain highly VGLUT-selective inhibitory activity, despite their reduction in potency, and exhibit no significant cellular toxicity. Potential use of this molecular modification is discussed.

Keywords

Brilliant Yellow; Cytotoxicity; Structural modification; VGLUT-selective inhibition; Vesicular glutamate uptake.

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