Preti, Delia; Baraldi, Pier Giovanni; Saponaro, Giulia; Romagnoli, Romeo; Tabrizi, Mojgan Aghazadeh; Baraldi, Stefania; Cosconati, Sandro; Bruno, Agostino; Novellino, Ettore; Vincenzi, Fabrizio; Ravani, Annalisa; Borea, Pier Andrea; Varani, Katia
Design, Synthesis, and Biological Evaluation of Novel 2-((2-4-(Substituted)phenylpiperazin-1-yl)ethyl)amino)-5 '-N-ethylcarboxamidoadenosines as Potent and Selective Agonists of the A(2A) Adenosine Receptor

Stimulation of A(2A) adenosine receptors (AR) promotes anti-inflammatory responses in animal models of allergic rhinitis, asthma, chronic obstructive pulmonary disease, and rheumatic diseases. Herein we describe the results of a research program aimed at identifying potent and selective agonists of the A(2A)AR as potential anti-inflammatory agents. The recent crystallographic analysis of A(2A)AR agonists and antagonists in complex with the receptor provided key information on the structural determinants leading to receptor activation or blocking. In light of this, we designed a new series of 2-((4-aryl(alkyl)piperazin-1-yl)alkylamino)-5'-N-ethylcarboxamidoadenosi nes with high A(2A)AR affinity, activation potency and selectivity obtained by merging distinctive structural elements of known agonists and antagonists of the investigated target. Docking-based SAR optimization allowed us to identify compound 42 as one of the most potent and selective A(2A) agonist discovered so far (K-i hA(2A)AR = 4.8 nM, EC50 hA(2A)AR = 4.9 nM, K-i hA(1)AR > 10.000 nM, K-i hA(3)AR = 1487 nM, EC50 hA(2B)AR > 10 000 nM).


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