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

Sagit Azran; Daniel Förster; Ortal Danino; Yael Nadel; Georg Reiser; Bilha Fischer

doi:10.1021/jm400197m

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

J Med Chem. 2013 Jun 27;56(12):4938-52. doi: 10.1021/jm400197m. Epub 2013 Jun 10.

Authors

Sagit Azran¹, Daniel Förster, Ortal Danino, Yael Nadel, Georg Reiser, Bilha Fischer

Affiliation

¹ Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.

PMID: 23751098
DOI: 10.1021/jm400197m

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

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

Substances

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