International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update

Abstract

In the 10 years since our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors, no developments have led to major changes in the recommendations. However, there have been so many other developments that an update is needed. The fact that the structure of one of the adenosine receptors has recently been solved has already led to new ways of in silico screening of ligands. The evidence that adenosine receptors can form homo- and heteromultimers has accumulated, but the functional significance of such complexes remains unclear. The availability of mice with genetic modification of all the adenosine receptors has led to a clarification of the functional roles of adenosine, and to excellent means to study the specificity of drugs. There are also interesting associations between disease and structural variants in one or more of the adenosine receptors. Several new selective agonists and antagonists have become available. They provide improved possibilities for receptor classification. There are also developments hinting at the usefulness of allosteric modulators. Many drugs targeting adenosine receptors are in clinical trials, but the established therapeutic use is still very limited.

Fig. 1.

Left, crystal structure of the adenosine A_2A receptor. Brown, α-helical elements; dark blue, ZM241385; yellow, disulfide bridges; pink, extracellular domain; red, stearic acid molecules; and light blue, intracellular domain. Membrane boundaries are represented as ellipsoids. Right, ligand binding site of the adenosine A_2A receptor. Brown, four transmembrane domains (helices 3, 5, 6, and 7); dark blue, ZM241385; blue spheres, explicit water molecules; pink, extracellular elements; yellow, disulfide bridges; and atom-coded colors, amino acid side chains involved in ligand binding.

Fig. 2.

Nonselective and A₁-selective agonists.

Fig. 3.

A_2A-selective agonists.

Fig. 4.

A_2B-selective agonists.

Fig. 5.

A₃-selective agonists.

Fig. 6.

Nonselective and A₁-selective antagonists.

Fig. 7.

A_2A-selective antagonists.

Fig. 8.

A_2B- selective antagonists.

Fig. 9.

A₃-selective antagonists.

Fig. 10.

Selected allosteric enhancers of action of agonist at the A₁ adenosine receptor (A) and at the A_2A receptor (B).

Fig. 11.

Bivalent ligand bridging orthosteric and allosteric site on the human A₁ adenosine receptor.

Fig. 12.

Structures of pyridinylisoquinoline and imidizoquinolinamine derivatives that act as PAMs of of the human A₃ adenosine receptor and structure of 2-AG, which acts as a NAM of the A₃ receptor.