Andrea Spinaci, Catia Lambertucci, Michela Buccioni, Diego Dal Ben, Claudia Graiff, Maria Cristina Barbalace, Silvana Hrelia, Cristina Angeloni, Seyed Khosrow Tayebati, Massimo Ubaldi, Alessio Masi, Karl-Norbert Klotz, Rosaria Volpini, Gabriella Marucci

• The A\(_{2A}\) adenosine receptor (A\(_{2A}\)AR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive tools for neurodegenerative disorders. In order to find novel A\(_{2A}\)AR ligands, two series of compounds based on purine and triazolotriazine scaffolds were synthesized and tested at ARs. Compound 13 was also tested in an in vitro model of neuroinflammation. Some compounds were found to possess high affinity for A\(_{2A}\)AR, and it was observed thatThe A\(_{2A}\) adenosine receptor (A\(_{2A}\)AR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive tools for neurodegenerative disorders. In order to find novel A\(_{2A}\)AR ligands, two series of compounds based on purine and triazolotriazine scaffolds were synthesized and tested at ARs. Compound 13 was also tested in an in vitro model of neuroinflammation. Some compounds were found to possess high affinity for A\(_{2A}\)AR, and it was observed that compound 13 exerted anti-inflammatory properties in microglial cells. Molecular modeling studies results were in good agreement with the binding affinity data and underlined that triazolotriazine and purine scaffolds are interchangeable only when 5- and 2-positions of the triazolotriazine moiety (corresponding to the purine 2- and 8-positions) are substituted.…