Pharmacophore-based discovery of substituted pyridines as novel dopamine transporter inhibitors.
Bioorg Med Chem Lett
; 13(3): 513-7, 2003 Feb 10.
Article
en En
| MEDLINE
| ID: mdl-12565962
ABSTRACT
Abnormal dopamine signaling in brain has been implicated in several conditions such as cocaine abuse, Parkinson's disease and depression. Potent and selective dopamine transporter inhibitors may be useful as pharmacological tools and therapeutic agents. Simple substituted pyridines were discovered as novel dopamine transporter (DAT) inhibitors through pharmacophore-based 3D-database search. The most potent compound 18 has a K(i) value of 79 nM in inhibition of WIN35,248 binding to dopamine transporter and 255 nM in inhibition of dopamine reuptake, respectively, as potent as cocaine. Preliminary structure-activity relationship studies show that the geometry and the nature of the substituents on the pyridine ring determine the inhibitory activity and selectivity toward the three monoamine transporters. The substituted pyridines described herein represent a class of novel DAT inhibitors with simple chemical structures and their discovery provides additional insights into the binding site of DAT.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas de Transporte de Membrana
/
Piridinas
/
Simportadores
/
Moduladores del Transporte de Membrana
/
Proteínas del Tejido Nervioso
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2003
Tipo del documento:
Article
País de afiliación:
Estados Unidos