Fig. 5.

Functional selectivity of the adenosine A ₃ receptor. Ligands with a bias towards β-arrestin-mediated signaling versus a Gα _i-dependent pathway have been identified. Ligands that are antagonists for Gα _i-mediated cAMP inhibition such as DMPA, CCPA, MRS1760, and MRS542 act as partial agonists for β-arrestin translocation. Interestingly, amongst the compounds that act as full agonists for both pathways, i.e., NECA, MRS3558, IB-MECA, Cl-IB-MECA, CGS21680, and CPA, both the nonspecific agonist NECA and the A₃R-specific agonist MRS3558 show faster β-arestin translocation rates. DBXRM, a full agonist for the Gα _i pathway, was a partial agonist for β-arrestin signaling. Besides these evident examples of functional selectivity, there are conflicting reports of the effects A₃R ligands have on apoptosis and proliferation. Since in many of these studies very high ligand concentrations were used, care must be taken when drawing conclusions about biased effects on cell growth. See references in the text for more detailed information