Medicinal chemistry of a _2B adenosine receptors

A _2B adenosine receptors (A _2B ARs) 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 _2B AR antagonists include inflammatory (pulmonary, colon) and autoimmune diseases, pain, fibrosis, infectious diseases, diabetes, and more. Agonists were found to exhibit cardioprotective properties. The A _2B AR is most closely related to the A _2A AR subtype. Both are G _s protein-coupled receptors, but the A _2B AR is additionally coupled to G _q proteins. A _2B AR expression is upregulated under pathological conditions (hypoxia, inflammation, ischemia) and on many cancer cells. A _2B ARs form stable heteromeric complexes with A _2A ARs when co-expressed, and thereby completely block A _2A AR signaling. There is still a lack of potent, selective, and fully efficacious A _2B AR agonists, while structurally diverse potent and selective competitive antagonists for A _2B ARs have become available. The first positive and negative allosteric modulators for A _2B ARs were recently described. For the labeling of A _2B ARs, antagonist radioligands have been developed, and recently the first potent and selective fluorescent ligands were reported.