The structure of the adenosine receptors: implications for drug discovery

Extracellular adenosine mediates most of its physiological effects via an interaction with four G protein-coupled receptors (GPCRs), the adenosine receptors (ARs). These ARs are important pharmacological targets in the treatment of a wide variety of diseases from central nervous system disorders to ischemic injury. As for other GPCRs, drug development for the ARs has been hampered by the lack of structural data for this class of membrane proteins. However, in the past 3 years, this situation has changed with the elucidation of structures for the turkey β(1)-adrenoceptor, the human β(2)-adrenoceptor, squid rhodopsin, the activated form of bovine (rhod)opsin, the human adenosine A(2A) receptor, and most recently the CXCR4 chemokine receptor. In this review, the structural features of the human adenosine A(2A) receptor will be discussed with a particular focus on the ligand binding site. Further, the implications of this structural information for AR ligand selectivity, drug screening, homology modeling, and virtual ligand screening will be discussed.