title: 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: Institut für Neurobiochemie, Medizinische Fakultät, Otto-von-Guericke Universität, Leipziger Str. 44, 39120 Magdeburg, Germany.
authors: Michael
authors: M
authors: Haas
authors: Department of Chemistry, Gonda-Goldschmied Medical Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors: Tamar
authors: T
authors: Ginsburg-Shmuel
authors: Department of Chemistry, Gonda-Goldschmied Medical Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors: Bilha
authors: B
authors: Fischer
authors: Institut für Neurobiochemie, Medizinische Fakultät, Otto-von-Guericke Universität, Leipziger Str. 44, 39120 Magdeburg, Germany. Electronic address: georg.reiser@med.ovgu.de.
authors: Georg
authors: G
authors: Reiser
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001896:Boron Compounds / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D058910:Purinergic P2 Receptor Agonists / Q000494:pharmacology*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014500:Uracil Nucleotides / Q000737:chemistry / Q000494:pharmacology*; D014530:Uridine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D001896:Boron Compounds; D018696:Neuroprotective Agents; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; C000596649:Rp-5-OMe-uridine 5'-O-alpha-boranodiphosphate; D014409:Tumor Necrosis Factor-alpha; D014500:Uracil Nucleotides; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate
keywords: Apoptosis; P2Y(6) receptor; Protection; Purinergic agonist; TNFα