Highly efficient biocompatible neuroprotectants with dual activity as antioxidants and P2Y receptor agonists.
J Med Chem
; 56(12): 4938-52, 2013 Jun 27.
Article
em En
| MEDLINE
| ID: mdl-23751098
ABSTRACT
Currently, there is a need for novel, biocompatible, and effective neuroprotectants for the treatment of neurodegenerative diseases and brain injury associated with oxidative damage. Here, we developed nucleotide-based neuroprotectants acting dually as antioxidants and P2Y-R agonists. To improve the potency, selectivity, and metabolic stability of ATP/ADP, we substituted adenine C2-position by Cl and Pα/Pß position by borano group, 6-9. Nucleotides 6-9 inhibited oxidation in cell-free systems (Fe(II)-H2O2), as detected by ESR (IC50 up to 175 µM), and ABTS assay (IC50 up to 40 µM). They also inhibited FeSO4-induced oxidative stress in PC12 cells (IC50 of 80-200 nM). 2-Cl-ADP(α-BH3), 7a, was found to be the most potent P2Y1-R agonist currently known (EC50 7 nM) and protected primary cortical neurons from FeSO4 insult (EC50 170 nM). In addition, it proved to be metabolically stable in human blood serum (t(1/2) 7 vs 1.5 h for ADP). Hence, we propose 7a as a highly promising neuroprotectant.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Materiais Biocompatíveis
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Fármacos Neuroprotetores
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Receptores Purinérgicos P2Y
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Agonistas do Receptor Purinérgico P2Y
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Antioxidantes
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Nucleotídeos
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2013
Tipo de documento:
Article