Design and synthesis of novel dual-action compounds targeting the adenosine A(2A) receptor and adenosine transporter for neuroprotection.
ChemMedChem
; 6(8): 1390-400, 2011 Aug 01.
Article
en En
| MEDLINE
| ID: mdl-21692183
ABSTRACT
A novel compound, N6-(4-hydroxybenzyl)adenosine, isolated from Gastrodia elata and which has been shown to be a potential therapeutic agent for preventing and treating neurodegenerative disease, was found to target both the adenosine A(2A) receptor (A(2A) R) and the equilibrative nucleoside transporter 1 (ENT1). As A(2A) R and ENT1 are proximal in the synaptic crevice of striatum, where the mutant huntingtin aggregate is located, the dual-action compounds that concomitantly target these two membrane proteins may be beneficial for the therapy of Huntington's disease. To design the desired dual-action compounds, pharmacophore models of the A(2A) R agonists and the ENT1 inhibitors were constructed. Accordingly, potentially active compounds were designed and synthesized by chemical modification of adenosine, particularly at the N6 and C5' positions, if the predicted activity was within an acceptable range. Indeed, some of the designed compounds exhibit significant dual-action properties toward both A(2A) R and ENT1. Both pharmacophore models exhibit good statistical correlation between predicted and measured activities. In agreement with competitive ligand binding assay results, these compounds also prevent apoptosis in serum-deprived PC12 cells, rendering a crucial function in neuroprotection and potential utility in the treatment of neurodegenerative diseases.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Adenosina
/
Fármacos Neuroprotectores
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Tranportador Equilibrativo 1 de Nucleósido
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Receptor de Adenosina A2A
/
Agonistas del Receptor de Adenosina A2
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
ChemMedChem
Asunto de la revista:
FARMACOLOGIA
/
QUIMICA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Taiwán