International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

Abstract

Our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors (2011) contained a number of emerging developments with respect to this G protein-coupled receptor subfamily, including protein structure, protein oligomerization, protein diversity, and allosteric modulation by small molecules. Since then, a wealth of new data and results has been added, allowing us to explore novel concepts such as target binding kinetics and biased signaling of adenosine receptors, to examine a multitude of receptor structures and novel ligands, to gauge new pharmacology, and to evaluate clinical trials with adenosine receptor ligands. This review should therefore be considered a further update of our previous reports from 2001 and 2011. SIGNIFICANCE STATEMENT: Adenosine receptors (ARs) are of continuing interest for future treatment of chronic and acute disease conditions, including inflammatory diseases, neurodegenerative afflictions, and cancer. The design of AR agonists ("biased" or not) and antagonists is largely structure based now, thanks to the tremendous progress in AR structural biology. The A_2A- and A_2BAR appear to modulate the immune response in tumor biology. Many clinical trials for this indication are ongoing, whereas an A_2AAR antagonist (istradefylline) has been approved as an anti-Parkinson agent.

Fig. 1

Selected ligands for studying ARs.

Fig. 2

Ligands investigated in kinetic studies.

Fig. 3

Ligands in 3D receptor structures and ligands in biased signaling studies. (Note: In 67 and 68, the X-ray structure of “LUAA47070” was not obtained with the prodrug LUAA47070 but with the A_2AAR antagonist that is released from the prodrug upon hydrolysis.)

Fig. 4

Overview of the A_2AAR binding site, showing the first frame of two movies: (A) antagonist (Supplemental Video 1) and (B) agonist (Supplemental Video 2). All residues within 2Å of a given ligand in an A_2AAR structure were considered as the binding pocket, and this selection was maintained in all frames. The residues are labeled according to the wild-type (WT) sequence, and modifications made to the receptor (e.g., the thermostabilizing mutant S277^7.42A) are not taken into account; note that no labeling is used in the supplemental movie files. The Ballesteros-Weinstein numbering is given in superscript. Ligands are shown in orange, with a volumetric occupancy surface-colored on the atom type. Water atoms in the binding site are shown as red dots, and the sodium ion (when present) as a purple sphere. If alternate coordinates were given in the extracted PDB file, the ‘A’ coordinates were maintained, except in the case of caffeine, in which case we generated two separate frames (referred to as 5mzpa and 5mzpb) to show the two binding modes in the crystal structure. Only distinctly different binding modes of ZM241385 (as present in 4EIY and 3PWH) are included in the movie.

Fig. 5

Ligands in clinical studies.