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

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 P_α/P_β 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.