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/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.
MeSH terms
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Animals
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Antioxidants / chemistry
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Antioxidants / metabolism
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Antioxidants / pharmacology*
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Antioxidants / toxicity
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Biocompatible Materials / chemistry
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Biocompatible Materials / metabolism
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Biocompatible Materials / pharmacology*
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Biocompatible Materials / toxicity
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Drug Design
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Drug Stability
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Humans
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Hydrolysis
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Models, Molecular
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / metabolism
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Neuroprotective Agents / pharmacology*
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Neuroprotective Agents / toxicity
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Nucleotides / chemistry
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Nucleotides / metabolism
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Nucleotides / pharmacology*
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Nucleotides / toxicity
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PC12 Cells
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Protein Conformation
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Purinergic P2Y Receptor Agonists / chemistry
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Purinergic P2Y Receptor Agonists / metabolism
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Purinergic P2Y Receptor Agonists / pharmacology*
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Purinergic P2Y Receptor Agonists / toxicity
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Rats
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Reactive Oxygen Species / metabolism
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Receptors, Purinergic P2Y / chemistry
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Receptors, Purinergic P2Y / metabolism*
Substances
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Antioxidants
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Biocompatible Materials
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Neuroprotective Agents
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Nucleotides
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Purinergic P2Y Receptor Agonists
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Reactive Oxygen Species
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Receptors, Purinergic P2Y