Figure 1. Effects of adenosine A2A receptor agonism. Activation of the adenosine A2A receptor (ADORA2A) is known to both inhibit inflammatory processes and promote vasodilation. The cell surface enzyme ecto-5ʹ-nucleotidase (NT5E; NT; CD73) is highly expressed by immune cells and endothelial cells and is one of the central regulators of endogenous adenosine signaling. CD73 dephosphorylates adenosine monophosphate (AMP) to form adenosine.

(I) In immune cells, adenosine signaling through ADORA2A inhibits proinflammatory processes.

(II) In endothelial cells, adenosine signaling through ADORA2A promotes vasodilation.

In Flögel et al., researchers showed that their ADORA2A agonist prodrug is selectively activated at sites of inflammation, at which CD73 is highly upregulated. Thus, the molecule is able to exert potent anti-inflammatory effects at doses that do not also cause vasodilation.