A_2A adenosine receptor agonists, antagonists, inverse agonists and partial agonists

The Gs-coupled A_2A adenosine receptor (A_2AAR) has been explored extensively as a pharmaceutical target, which has led to numerous clinical trials. However, only one selective A_2AAR agonist (regadenoson, Lexiscan) and one selective A_2AAR antagonist (istradefylline, Nouriast) have been approved by the FDA, as a pharmacological agent for myocardial perfusion imaging (MPI) and as a cotherapy for Parkinson's disease (PD), respectively. Adenosine is widely used in MPI, as Adenoscan. Despite numerous unsuccessful clinical trials, medicinal chemical activity around A_2AAR ligands has accelerated recently, particularly through structure-based drug design. New drug-like A_2AAR antagonists for PD and cancer immunotherapy have been identified, and many clinical trials have ensued. For example, imaradenant (AZD4635), a compound that was designed computationally, based on A_2AAR X-ray structures and biophysical mapping. Mixed A_2AAR/A_2BAR antagonists are also hopeful for cancer treatment. A_2AAR antagonists may also have potential as neuroprotective agents for treatment of Alzheimer's disease.