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.

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

“…Methylene or halomethylene bridges, such as in antagonist 12 or agonist 14, are tolerated at some of the P2YRs (Das et al, 2010;Yelovitch et al, 2012). Boronation of the a-phosphate of ADP derivatives is conducive to activity at the P2Y 1 R; a pure stereoisomer of the 2-Cl member of that series displayed an EC 50 of 7 nM (Azran et al, 2013). Although P2Y 6 R prefers UDP over UTP, various 59-triphosphate analogs have proven to be potent (Maruoka et al, 2010).…”

Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues

“…Fischer et al. reported 2‐chloro‐adenosine‐5′‐ O ‐α‐boranodiphosphate (2‐Cl‐α‐BH 3 ‐ADP) as a potent agonist (EC 50  = 7 n m ) of P2Y1 receptor, whose endogenous substrate is adenosine diphosphate (ADP) 38. Similarly, 2‐methylthio‐AMP was reported as an inhibitor of P2Y12 receptor, for which ADP serves as the endogenous substrate as well 39, 40.…”

Co-administration effects of α-lipoic acid and nucleo CMP on arousal and sensory cortical activity

“…16 Additionally, lipoic acid produced cytoprotective effects in cerebral ischemic reperfusion injury via direct antioxidant effects or through activation of endogenous glutathione and/or elevation of vitamins E and C. 17 A deficiency in cerebral glutathione leads to deterioration in cognitive function, spatial memory and psychomotor performance moreover; lipoic acid chelators lead to significant deterioration and declining in and proliferation of neuronal stem cells, which may be related to the activation of mitogen activated protein kinase (MAPK) pathway that lead to cellular proliferation via upregulation of purinergic receptor (P2Y. 25 Nucleo CMP also leads to significant dopaminergic neuronal activation and neuroprotection via preservation of mitochondrial transition pore depolarization from ischemic hypoxic neuronal injury and prevention of glutamate-induced neurotoxicity. 26 Therefore, nucleo CMP produced significant cognitive and arousal enhancement effects due to activation of purinergic and dopaminergic receptors or/and modulation of glutaminergic neurotransmission, this may explained the stimulatory effects of nucleo CMP on critical flicker-fusion frequency which reflects improvement in arousal and sensory function.…”