Medicinal chemistry of the A ₃ adenosine receptor

Numerous structure-activity relationship (SAR) studies of ligands of the A ₃ adenosine receptor (AR) have generated selective agonists, antagonists, partial agonists, and allosteric modulators. The efficacy of nucleoside agonists may be reduced, while retaining affinity, by successive structural changes. Subnanomolar affinity and selectivity of >10,000-fold have been achieved for various compound classes, but often with a pronounced species dependence, especially for diverse heterocyclic antagonists. Two prototypical A ₃ AR agonists, IB-MECA and Cl-IB-MECA, are being evaluated clinically for treating autoimmune inflammatory disorders and liver diseases. The design of A ₃ AR orthosteric ligands is now largely guided by computational approaches, in which the receptor is modeled by homology to X-ray structures of the A _2A AR and other G protein-coupled receptors (GPCRs). Thus, we have amassed a large body of data concerning the relationship of receptor structure and function and have supported many of the hypotheses generated with experimental data.