Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine Derivatives with High Affinity for Both the Adenosine A 1 and A 2A Receptors, and Efficacy in Animal Models of Depression

New compounds with a 7-amino-2-arylmethyl-thiazolo[5,4-d]pyrimidine structure were synthesized and evaluated in vitro for their affinity and/or potency at the human (h) A 1 , hA 2A , hA 2B , and hA 3 adenosine receptors (ARs). Several compounds ( 5 , 8 – 10 , 13 , 18 , 19 ) were characterized by nanomolar and subnanomolar binding affinities for the hA 1 and the hA 2A AR, respectively. Results of molecular docking studies supported the in vitro results. The 2-(2-fluorobenzyl)-5-(furan-2yl)-thiazolo[5,4-d]pyrimidin-7-amine derivative 18 (hA 1 K i = 1.9 nM; hA 2A K i = 0.06 nM) was evaluated for its antidepressant-like activity in in vivo studies, the forced swimming test (FST), the tail suspension test (TST), and the sucrose preference test (SPT) in mice, showing an effect comparable to that of the reference amitriptyline.