Highly efficient biocompatible neuroprotectants with dual activity as antioxidants and P2Y receptor agonists.

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.

• Authors: Sagit Azran, Daniel Förster, Ortal Danino, Yael Nadel, Georg Reiser, Bilha Fischer
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 12 Pg. 4938-52 (Jun 27 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23751098 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• Biocompatible Materials
• Neuroprotective Agents
• Nucleotides
• Purinergic P2Y Receptor Agonists
• Reactive Oxygen Species
• Receptors, Purinergic P2Y

Topics

• Animals
• Antioxidants (chemistry, metabolism, pharmacology, toxicity)
• Biocompatible Materials (chemistry, metabolism, pharmacology, toxicity)
• Drug Design
• Drug Stability
• Humans
• Hydrolysis
• Models, Molecular
• Neuroprotective Agents (chemistry, metabolism, pharmacology, toxicity)
• Nucleotides (chemistry, metabolism, pharmacology, toxicity)
• PC12 Cells
• Protein Conformation
• Purinergic P2Y Receptor Agonists (chemistry, metabolism, pharmacology, toxicity)
• Rats
• Reactive Oxygen Species (metabolism)
• Receptors, Purinergic P2Y (chemistry, metabolism)