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Adenosine is an endogenous purine nucleoside that plays a key role in numerous important physiological functions through interactions with specific cell-surface G-protein-coupled receptors (GPCRs), which are classified into four subtypes, namely A1, A2A, A2B, and A3 adenosine receptors (ARs).1−3

In 2001, we have described the synthesis and the biological evaluation of a class of 3-aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones (ATBIs) as a new class of selective A1 adenosine receptor antagonists (AR).4
A2B ARs have been generally defined as “low-affinity ARs”due to their low affinity not only for the endogenous ligand but also for several typical agonists, in contrast with other AR subtypes.
Because of the involvement of the A2B adenosine receptor in various physiological and pathological processes, such as the glucose metabolism and the growth and development of some forms of cancer, selective and potent ligands antagonists for the A2B adenosine receptor are currently in development as candidates for the treatment of cancer, diabetic retinopathy, etc..

Starting from the structure of ATBIs I worked on the development of two regioisomers, bearing a fluorescent group, the 4-Chloro-7-nitrobenzofurazan (NBD). I use this group because its small size does not generally affect affinity of the parent ligand. Moreover, NBD-containing compounds typically exhibit a low quantum yield in an aqueous solution, but they become highly fluorescent in nonpolar solvents or when bound to membranes or to hydrophobic clefts in proteins.

(1) Poulsen, S. A.; Quinn, R. J. Adenosine receptors: new opportunities for future drugs. Bioorg. Med. Chem. 1998, 6, 619−641.
(2) Fredholm, B. B.; Arslan, G.; Halldner, L.; Kull, B.; Schulte, G.; Wasserman, W. Structure and function of adenosine receptors and their genes. Naunyn Schmiedeberg's Arch. Pharmacol. 2000, 362, 364−374.
(3) Fredholm, B. B.; IJzerman., A. P.; Jacobson, K. A.; Klotz, K.-N.; Linden, J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 2001, 53, 527−532.
(4) Da Settimo, F.; Primofiore, G.; Taliani, S.; Marini, A. M.; La Motta, C.; Novellino, E.; Greco, G.; Lavecchia, A.; Trincavelli, L.; Martini, C. 3-Aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: a new class of selective A1 adenosine receptor antagonists. J. Med. Chem. 2001, 44, 316−327.