Highly efficient biocompatible neuroprotectants with dual activity as antioxidants and P2Y receptor agonists
| Autor: | Bilha Fischer, Yael Nadel, Daniel Förster, Ortal Danino, Sagit Azran, Georg Reiser |
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| Rok vydání: | 2013 |
| Předmět: |
Agonist
Models Molecular P2Y receptor medicine.drug_class Protein Conformation Biocompatible Materials medicine.disease_cause PC12 Cells Antioxidants chemistry.chemical_compound Drug Stability Drug Discovery medicine Animals Humans Nucleotide Receptor IC50 EC50 chemistry.chemical_classification ABTS Chemistry Nucleotides Hydrolysis Rats Neuroprotective Agents Biochemistry Drug Design Receptors Purinergic P2Y Molecular Medicine Purinergic P2Y Receptor Agonists Reactive Oxygen Species Oxidative stress |
| Zdroj: | Journal of medicinal chemistry. 56(12) |
| ISSN: | 1520-4804 |
| Popis: | 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/Pβ 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. |
| Databáze: | OpenAIRE |
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