Medicinal chemistry of a_2B adenosine receptors

A_2B adenosine receptors (A_2BARs) are in the focus of interest as drug targets in (immuno)oncology since antagonists show anti-proliferative, anti-angiogenic, anti-metastatic, and immunostimulatory properties. Additional (poten-tial) indications for A_2BAR antagonists include inflammatory (pulmonary, colon) and autoimmune diseases, pain, fibrosis, infectious diseases, diabetes, and more. Agonists were found to exhibit cardioprotective properties. The A_2BAR is most closely related to the A_2AAR subtype. Both are G_s protein-coupled receptors, but the A_2BAR is additionally coupled to G_q proteins. A_2BAR expression is upregulated under pathological conditions (hypoxia, inflammation, ischemia) and on many cancer cells. A_2BARs form stable heteromeric complexes with A_2AARs when co-expressed, and thereby completely block A_2AAR signaling. There is still a lack of potent, selective, and fully efficacious A_2BAR agonists, while structurally diverse potent and selective competitive antagonists for A_2BARs have become available. The first positive and negative allosteric modulators for A_2BARs were recently described. For the labeling of A_2BARs, antagonist radioligands have been developed, and recently the first potent and selective fluorescent ligands were reported.