Design, synthesis and biological evaluation of small-azo-dyes as potent Vesicular Glutamate Transporters inhibitors.
|Title||Design, synthesis and biological evaluation of small-azo-dyes as potent Vesicular Glutamate Transporters inhibitors.|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Favre-Besse F-C, Poirel O, Bersot T, Kim-Grellier E, Daumas S, Mestikawy SEl, Acher FC, Pietrancosta N|
|Journal||Eur J Med Chem|
|Date Published||2014 May 6|
|Keywords||Animals, Azo Compounds, Coloring Agents, Dose-Response Relationship, Drug, Drug Design, Molecular Structure, Rats, Structure-Activity Relationship, Vesicular Glutamate Transport Proteins|
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.
|Alternate Journal||Eur J Med Chem|