title: Design, synthesis and biological evaluation of small-azo-dyes as potent Vesicular Glutamate Transporters inhibitors.
abstract: Vesicular Glutamate Transporters (VGLUTs) allow the loading of presynapic glutamate vesicles and thus play a critical role in glutamatergic synaptic transmission. VGLUTs have proved to be involved in several major neuropathologies and directly correlated to clinical dementia in Alzheimer and Parkinson's disease. Accordingly VGLUT represent a key biological target or biomarker for neuropathology treatment or diagnostic. Yet, despite the pivotal role of VGLUTs, their pharmacology appears quite limited. Known competitive inhibitors are restricted to some dyes as Trypan Blue (TB) and glutamate mimics. This lack of pharmacological tools has heavily hampered VGLUT investigations. Here we report a rapid access to small molecules that combine benefits of TB and dicarboxylic quinolines (DCQs). Their ability to block vesicular glutamate uptake was evaluated. Several compounds displayed low micromolar inhibitory potency when size related compounds are thirty to forty times less potent (i.e. DCQ). We then confirmed the VGLUT selectivity by measuring the effect of the series on vesicular monoamine transport and on metabotropic glutamate receptor activity. These inhibitors are synthesized in only two steps and count among the best pharmacological tools for VGLUTs studies.
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Saints-Pères, 75270 Paris 06, France.
authors.forename: Franck-Cyril
authors.initials: FC
authors.lastname: Favre-Besse
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U952, Université Pierre et Marie Curie, 9 quai Saint Bernard, 75005 Paris, France; Centre National de la Recherche Scientifique (CNRS) UMR 7224, 9 quai Saint Bernard, 75005 Paris, France; Université Pierre et Marie Curie (UPMC) Paris 06, Pathophysiology of Central Nervous System Disorders, 9 quai Saint Bernard, 75005 Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Poirel
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U952, Université Pierre et Marie Curie, 9 quai Saint Bernard, 75005 Paris, France; Centre National de la Recherche Scientifique (CNRS) UMR 7224, 9 quai Saint Bernard, 75005 Paris, France; Université Pierre et Marie Curie (UPMC) Paris 06, Pathophysiology of Central Nervous System Disorders, 9 quai Saint Bernard, 75005 Paris, France.
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Bersot
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U952, Université Pierre et Marie Curie, 9 quai Saint Bernard, 75005 Paris, France; Centre National de la Recherche Scientifique (CNRS) UMR 7224, 9 quai Saint Bernard, 75005 Paris, France; Université Pierre et Marie Curie (UPMC) Paris 06, Pathophysiology of Central Nervous System Disorders, 9 quai Saint Bernard, 75005 Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Kim-Grellier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U952, Université Pierre et Marie Curie, 9 quai Saint Bernard, 75005 Paris, France; Centre National de la Recherche Scientifique (CNRS) UMR 7224, 9 quai Saint Bernard, 75005 Paris, France; Université Pierre et Marie Curie (UPMC) Paris 06, Pathophysiology of Central Nervous System Disorders, 9 quai Saint Bernard, 75005 Paris, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Daumas
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U952, Université Pierre et Marie Curie, 9 quai Saint Bernard, 75005 Paris, France; Centre National de la Recherche Scientifique (CNRS) UMR 7224, 9 quai Saint Bernard, 75005 Paris, France; Université Pierre et Marie Curie (UPMC) Paris 06, Pathophysiology of Central Nervous System Disorders, 9 quai Saint Bernard, 75005 Paris, France; Douglas Hospital Research Center, Department of Psychiatry, McGill University, 6875 boulevard Lasalle Verdun, QC, Canada.
authors.forename: Salah
authors.initials: S
authors.lastname: El Mestikawy
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Saints-Pères, 75270 Paris 06, France. Electronic address: francine.acher@parisdescartes.fr.
authors.forename: Francine C
authors.initials: FC
authors.lastname: Acher
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Saints-Pères, 75270 Paris 06, France. Electronic address: Nicolas.pietrancosta@parisdescartes.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pietrancosta
mesh_terms: D000818:Animals; D001391:Azo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004396:Coloring Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D050496:Vesicular Glutamate Transport Proteins / Q000037:antagonists & inhibitors*
chemical_list: D001391:Azo Compounds; D004396:Coloring Agents; D050496:Vesicular Glutamate Transport Proteins
keywords: Azo dye; Glutamate; Inhibitors; Neurotransmitter; VGLUT; Vesicular uptake