title: 3-(Fur-2-yl)-10-(2-phenylethyl)-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one, a novel adenosine receptor antagonist with A(2A)-mediated neuroprotective effects.
abstract: In this study, compound FTBI (3-(2-furyl)-10-(2-phenylethyl)[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one) was selected from a small library of triazinobenzimidazole derivatives as a potent A(2A) adenosine receptor (AR) antagonist and tested for its neuroprotective effects against two different kinds of dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium (MPP+) and methamphetamine (METH), in rat PC12 and in human neuroblastoma SH-SY5Y cell lines. FTBI, in a concentration range corresponding to its affinity for A(2A) AR subtype, significantly increased the number of viable PC12 cells after their exposure to METH and, to a similar extent, to MPP+, as demonstrated in both trypan blue exclusion assay and in cytological staining. These neuroprotective effects were also observed with a classical A(2A) AR antagonist, ZM241385, and appeared to be completely counteracted by the AR agonist, NECA, supporting A(2A) ARs are directly involved in FTBI-mediated effects. Similarly, in human SH-SY5Y cells, FTBI was able to prevent cell toxicity induced by MPP+ and METH, showing that this A(2A) AR antagonist has a neuroprotective effect independently by the specific cell model. Altogether these results demonstrate that the A(2A) AR blockade mediates cell protection against neurotoxicity induced by dopaminergic neurotoxins in dopamine containing cells, supporting the potential use of A(2A) AR antagonists in dopaminergic degenerative diseases including Parkinson's disease.
authors.affiliation: Dipartimento di Morfologia Umana e Biologia Applicata, Università di Pisa, Via Roma 55, 56126 Pisa, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Scatena
authors.forename: Francesco
authors.initials: F
authors.lastname: Fornai
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.forename: Isabella
authors.initials: I
authors.lastname: Pugliesi
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival; D003198:Computer Simulation; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D008566:Membranes / Q000378:metabolism; D008694:Methamphetamine / Q000633:toxicity; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D016716:PC12 Cells; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000187:drug effects* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D014227:Triazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C579628:3-(fur-2-yl)-10-(2-phenylethyl)-(1,2,4)triazino(4,3-a)benzimidazol-4(10H)-one; D058917:Adenosine A2 Receptor Antagonists; D001562:Benzimidazoles; D007202:Indicators and Reagents; D018696:Neuroprotective Agents; D009498:Neurotoxins; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; D008694:Methamphetamine; D000242:Cyclic AMP; D015655:1-Methyl-4-phenylpyridinium