title: Vesicular Glutamate Transporter Inhibitors: Structurally Modified Brilliant Yellow Analogs.
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.
authors.affiliation: Molecular & Behavioral Neuroscience Institute, Medical School, University of Michigan, 109 Zina Pitcher, Ann Arbor, MI, 48109, USA.|IMS Consulting Group, 485 Lexington Ave, New York, NY, 10017, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Kehrl
authors.affiliation: Molecular & Behavioral Neuroscience Institute, Medical School, University of Michigan, 109 Zina Pitcher, Ann Arbor, MI, 48109, USA.
authors.forename: J Christian
authors.initials: JC
authors.lastname: Althaus
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI, 48109, USA. howalh@umich.edu.|Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI, 48109, USA. howalh@umich.edu.
authors.forename: Hollis D
authors.initials: HD
authors.lastname: Showalter
authors.affiliation: Cheminpharma LLC, 23 Business Park Drive, Branford, CT, 06405, USA.
authors.forename: DiAndra M
authors.initials: DM
authors.lastname: Rudzinski
authors.affiliation: Molecular & Behavioral Neuroscience Institute, Medical School, University of Michigan, 109 Zina Pitcher, Ann Arbor, MI, 48109, USA.|Department of Molecular and Integrative Physiology, Medical School, University of Michigan, 1150 West Medical Center Dr., Ann Arbor, MI, 48109, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sutton
authors.affiliation: Molecular & Behavioral Neuroscience Institute, Medical School, University of Michigan, 109 Zina Pitcher, Ann Arbor, MI, 48109, USA. tueda@med.umich.edu.|Department of Pharmacology, Medical School, University of Michigan, 2301 MSRB, 1150 West Medical Center Dr., Ann Arbor, MI, 48109, USA. tueda@med.umich.edu.|Department of Psychiatry, Medical School, University of Michigan, 1500 East Medical Center Dr., Ann Arbor, MI, 48104, USA. tueda@med.umich.edu.
authors.forename: Tetsufumi
authors.identifier: http://orcid.org/0000-0001-5968-7060
authors.initials: T
authors.lastname: Ueda
mesh_terms: D000818:Animals; D001391:Azo Compounds / Q000737:chemistry* / Q000378:metabolism*; D001557:Benzenesulfonates / Q000737:chemistry* / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D013572:Synaptic Vesicles / Q000737:chemistry / Q000378:metabolism; D050496:Vesicular Glutamate Transport Proteins / Q000032:analysis* / Q000378:metabolism*
chemical_list: D001391:Azo Compounds; D001557:Benzenesulfonates; D050496:Vesicular Glutamate Transport Proteins; C059622:Direct Yellow 4 dye
keywords: Brilliant Yellow; Cytotoxicity; Structural modification; VGLUT-selective inhibition; Vesicular glutamate uptake