Generation and screening of oxime libraries addressing the neuronal GABA transporter GAT1.
ChemMedChem
; 10(2): 396-410, 2015 Feb.
Article
en En
| MEDLINE
| ID: mdl-25369775
ABSTRACT
The objective of the present study was to transfer the concept of library screening by MS binding assays, so far applied to pseudostatic hydrazine libraries, to static oxime libraries to screen for new potent inhibitors of mGAT1, the most abundant GABA transporter in the central nervous system that represents a validated drug target for the treatment of epilepsy. Library generation was performed by reaction of guvacine derivatives possessing a hydroxylamine functionality with various sets of four aldehydes. After dilution, the libraries were screened by competitive MS binding assays. Deconvolution experiments allowed hits in the most active libraries to be identified, and they were resynthesized for biological evaluation. That way a series of compounds was identified that displayed binding affinities ≥8.00 (pKi ) at mGAT1, one of which was found to be the most potent mGAT1 inhibitor known to date in a functional GABA uptake assay with a pIC50 value of 8.27 ± 0.03.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Oximas
/
Proteínas Transportadoras de GABA en la Membrana Plasmática
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Límite:
Humans
Idioma:
En
Revista:
ChemMedChem
Asunto de la revista:
FARMACOLOGIA
/
QUIMICA
Año:
2015
Tipo del documento:
Article