Introduction to adenosine receptors as therapeutic targets

Abstract

Adenosine acts as a cytoprotective modulator in response to stress to an organ or tissue. Although short-lived in the circulation, it can activate four subtypes of G protein-coupled adenosine receptors (ARs): A(1), A(2A), A(2B), and A(3). The alkylxanthines caffeine and theophylline are the prototypical antagonists of ARs, and their stimulant actions occur primarily through this mechanism. For each of the four AR subtypes, selective agonists and antagonists have been introduced and used to develop new therapeutic drug concepts. ARs are notable among the GPCR family in the number and variety of agonist therapeutic candidates that have been proposed. The selective and potent synthetic AR agonists, which are typically much longer lasting in the body than adenosine, have potential therapeutic applications based on their anti-inflammatory (A(2A) and A(3)), cardioprotective (preconditioning by A(1) and A(3) and postconditioning by A(2B)), cerebroprotective (A(1) and A(3)), and antinociceptive (A(1)) properties. Potent and selective AR antagonists display therapeutic potential as kidney protective (A(1)), antifibrotic (A(2A)), neuroprotective (A(2A)), and antiglaucoma (A(3)) agents. AR agonists for cardiac imaging and positron-emitting AR antagonists are in development for diagnostic applications. Allosteric modulators of A(1) and A(3) ARs have been described. In addition to the use of selective agonists/antagonists as pharmacological tools, mouse strains in which an AR has been genetically deleted have aided in developing novel drug concepts based on the modulation of ARs.

Fig. 1

Interconversion of extracellular adenine nucleotides and adenosine and their associated signaling pathways. These molecules may originate from intracellular sources. For example, adenosine may cross the plasma membrane through an equilibrative nucleoside transporter (ENT)1. The four subtypes of adenosine receptors (ARs) are grouped according to effects on adenylate cyclase. Inosine at micromolar concentrations also activates the A₃AR. Various extracellular nucleotides activate seven subtypes of P2X receptors and eight subtypes of P2Y, which are not specified here. The ARs and P2Y receptors are G-protein-coupled receptors (GPCRs), while the P2X receptors are ionotropic receptors. The ectonucleoside triphosphate diphosphohydrolases NT-PDase1 and NTPDase2 are also known as CD39 (apyrase) and CD39L1, respectively. NTPDases3 and 8 (not shown) are also involved in breakdown of extracellular nucleotides

Fig. 2

X-ray crystallographic structure of the human A_2A adenosine receptor (AR), showing the bound antagonist ZM241385 (Jaakola et al. 2008). The structure of the A_2AAR is colored by region: N-terminus and transmembrane helical (TM) domain 1 in orange, TM2 in ochre, TM3 in yellow, TM4 in green, TM5 in cyan, TM6 in blue, TM7 and C-terminus in purple. The p-hydroxyphenylethyl moiety of the antagonist ligand points toward the exofacial side of the receptor

Fig. 3

Structures of selected adenosine receptor (AR) agonists. K_i values in binding are available in references (Baraldi et al. 2008; Jacobson and Gao 2006; Yan et al. 2003)

Fig. 4

Structures of selected adenosine receptor (AR) antagonists. K_i values in binding are available in references (Baraldi et al. 2008; Jacobson and Gao 2006)

Fig. 5

Allosteric modulators of adenosine receptors (ARs)