5-OMe-uridine-5'-O-(α-boranodiphosphate), a novel nucleotide derivative highly active at the human P2Y(6) receptor protects against death-receptor mediated glial apoptosis.

Abstract

P2Y receptors are activated by nucleotides and involved in numerous physiological/pathophysiological processes. However, investigations of specific P2Y receptor functions have been hampered by lack of suitable receptor agonists-antagonists. Recently, we identified the nucleotide 5-OMe-UDP as potent and selective agonist for human P2Y6 receptors. We studied a series of derivatives of this analog with a Pα-borano group substituting a non-bridging oxygen and found increased potency and receptor specificity. Rp-5-OMe-UDPαB (Rp-5-OMe-uridine 5'-O-α-boranodiphosphate) was most potent and selective in inducing intracellular calcium signaling in 1321N1 astrocytoma cells expressing the human P2Y6 receptor. Here, we investigated whether Rp-5-OMe-UDPαB evokes cell protection through human P2Y6 receptors. We tested a well-established model, tumor necrosis factor α (TNFα)-induced cell death in 1321N1 astrocytoma cells. Rp-5-OMe-UDPαB inhibited TNFα-induced cell death even stronger than UDP. These first data of a neuro-protective activity of the human P2Y6 receptor emphasize the potential of the stable, selective, and potent Rp-5-OMe-UDPαB analog for exploiting P2Y6 receptor-mediated cellular functions, like cytoprotection in human tissues, with suitability for future neuro-protective drug development.

• Authors: Michael Haas, Tamar Ginsburg-Shmuel, Bilha Fischer, Georg Reiser
• Journal: Neuroscience letters (Neurosci Lett) Vol. 578 Pg. 80-4 (Aug 22 2014) ISSN: 1872-7972 [Electronic] Ireland
• PMID: 24970757 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Boron Compounds
• Neuroprotective Agents
• Purinergic P2 Receptor Agonists
• Receptors, Purinergic P2
• Rp-5-OMe-uridine 5'-O-alpha-boranodiphosphate
• Tumor Necrosis Factor-alpha
• Uracil Nucleotides
• purinoceptor P2Y6
• Uridine Diphosphate

Topics

• Apoptosis (drug effects)
• Boron Compounds (pharmacology)
• Calcium Signaling (drug effects)
• Cell Line, Tumor
• Humans
• Neuroglia (drug effects, metabolism)
• Neuroprotective Agents (pharmacology)
• Purinergic P2 Receptor Agonists (pharmacology)
• Receptors, Purinergic P2 (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)
• Uracil Nucleotides (chemistry, pharmacology)
• Uridine Diphosphate (analogs & derivatives, pharmacology)