Design, synthesis and biological evaluation of small-azo-dyes as potent Vesicular Glutamate Transporters inhibitors.
Eur J Med Chem
; 78: 236-47, 2014 May 06.
Article
em En
| MEDLINE
| ID: mdl-24686010
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos Azo
/
Desenho de Fármacos
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Corantes
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Proteínas Vesiculares de Transporte de Glutamato
Limite:
Animals
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
França