International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors

Abstract

Four adenosine receptors have been cloned and characterized from several mammalian species. The receptors are named adenosine A(1), A(2A), A(2B), and A(3). The A(2A) and A(2B) receptors preferably interact with members of the G(s) family of G proteins and the A(1) and A(3) receptors with G(i/o) proteins. However, other G protein interactions have also been described. Adenosine is the preferred endogenous agonist at all these receptors, but inosine can also activate the A(3) receptor. The levels of adenosine seen under basal conditions are sufficient to cause some activation of all the receptors, at least where they are abundantly expressed. Adenosine levels during, e.g., ischemia can activate all receptors even when expressed in low abundance. Accordingly, experiments with receptor antagonists and mice with targeted disruption of adenosine A(1), A(2A), and A(3) expression reveal roles for these receptors under physiological and particularly pathophysiological conditions. There are pharmacological tools that can be used to classify A(1), A(2A), and A(3) receptors but few drugs that interact selectively with A(2B) receptors. Testable models of the interaction of these drugs with their receptors have been generated by site-directed mutagenesis and homology-based modelling. Both agonists and antagonists are being developed as potential drugs.

FIG. 1.

Dendrogram showing sequence similarity between cloned adenosine receptors. The figure is slightly redrawn from that available at http://www.gpcr.org/7tm/seq/007_001/001_007_001.TREE.html. This phylogenetic tree was automatically calculated by WHAT IF based on a neighbor-joining algorithm.

FIG. 2.

Protein backbone representations of the structures of bacteriorhodopsin (A) and rhodopsin (B) as retrieved from the Brookhaven Protein Data Bank (1C3W and 1F88, respectively).

FIG. 3.

Computer modeling of CPA (yellow), human A₁ adenosine receptor interactions. Only helices III (left) and VII (right) are shown (both in green) with relevant residues (half-bond colors).

FIG. 4.

Structures of reference compounds used to classify adenosine receptors. Panel A, structure of some non-selective and A₁ receptor-selective adenosine analogs; panel B, structure of adenosine analogs used to classify A_2A and A₃ receptors; panel C, structure of selected adenosine receptor antagonists.