Adenosine is an endogenous nucleoside generated locally in tissues under conditions of hypoxia, ischemia, or inflammation. It modulates a variety of physiological functions in many tissues including the brain and heart.^1,2 Adenosine exerts its actions via four specific adenosine receptors (also named P1 purinergic receptors): Adenosine A₁ Receptor (A₁AR), Adenosine A_2A Receptor (A_2AAR), Adenosine A_2B Receptor (A_2BAR), and Adenosine A₃ Receptor (A₃AR). All are integral membrane proteins and are members of the G protein-coupled receptor superfamily. They share a common structure of seven putative transmembrane domains, an extracellular -NH₂ terminus, cytoplasmic -COOH terminus, and a third intracellular loop important for binding G proteins.^1-3 The adenosine receptors can be distinguished on the basis of their differential selectivity for adenosine analogs.^1-3

Adenosine receptors control neurotransmitter release through the facilitatory A_2AAR and the inhibitory A₁AR.⁴ A_2AAR and A₁AR are the major adenosine receptor subtypes expressed in the central nervous system (CNS). A_2AAR is mainly expressed in the striatum on GABAergic striatopallidal neurons, while A₁AR is widely distributed throughout the CNS.^5,6

A_2AAR was suggested to play a critical role in attenuation of systemic inflammatory responses and prevention of extensive tissue damage.⁷ It was suggested that extracellular adenosine that accumulates in inflamed and damaged tissue may activate the A_2AAR expressed in immune cells leading to termination/inhibition of the immune response.⁷ It was further suggested that this same mechanism may protect tumors from antitumor T cells through an immunosuppressive signal generated by the activation of A_2AAR on T cells by extracellular adenosine produced from hypoxic cancerous tissues.⁸