5-OMe-uridine-5′-O-(α-boranodiphosphate), a novel nucleotide derivative highly active at the human P2Y6 receptor protects against death-receptor mediated glial apoptosis

• We investigate human P2Y6 nucleotide receptor-mediated cytoprotection.
• Stereoisomers of PαBH3-substituted nucleotides show increased potency and selectivity.
• We apply the novel, highly potent and selective P2Y6 receptor agonist 5-OMe-UDPαB.
• The human P2Y6 nucleotide receptor mediates protection against TNFα-induced apoptosis.
• P2Y6 receptor antagonist inhibits protection of 5-OMe-UDPαB against apoptosis.

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.