Abstract
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) A1, hA2A, hA2B, and hA3 adenosine receptors (ARs). Several compounds (5, 8–10, 13, 18, 19) were characterized by nanomolar and subnanomolar binding affinities for the hA1 and the hA2A 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 (hA1 Ki = 1.9 nM; hA2A Ki = 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.
Highlights
According to the Diagnostic and Statistical Manual of Mental Disorders, depression is characterized by depressed mood and anhedonia associated with symptoms that may include significant weight gain or loss, insomnia, psychomotor agitation or retardation, fatigue or loss of energy, diminished ability to think or concentrate, and recurrent thoughts of death or suicide [2]
The results showed that we reached our goal, since all final compounds 1–19 featured by the presence of an unsubstituted or ortho-substituted benzyl ring at position 2 of the bicyclic core, exhibited good to high binding affinities at both the A1 and A2A adenosine receptors (ARs) higher than those of the previously reported compound 20 bearing a phenyl ring at the same position
AR dual antagonists belonging to the 7-aminothiazolo[5,4-d]pyrimidine series
Summary
Depression may represent a risk factor for cancer [3], diabetes [4], and cardiovascular disorders [5,6], and shows comorbidity with several medical illness including serious CNS disorders such as Alzheimer’s (AD) and Parkinson’s disease (PD) [6,7], stroke [8], and chronic pain [9]. Commonly used medications are associated with adverse reactions difficult to tolerate including cardiovascular, anticholinergic, neurologic, gastrointestinal, and other side effects. Another big drawback of antidepressant therapy currently in use is that its full efficacy begins to appear only after 4–6 weeks of treatment or even more [10,11]. The search for novel therapeutic strategies for the treatment of depression disorders represents an important research priority
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