Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

Abstract

Adenosine is involved in a range of physiological and pathological effects through membrane-bound receptors linked to G proteins. There are four subtypes of adenosine receptors, described as A₁AR, A_2AAR, A_2BAR, and A₃AR, which are the center of cAMP signal pathway-based drug development. Several types of agonists, partial agonists or antagonists, and allosteric substances have been synthesized from these receptors as new therapeutic drug candidates. Research efforts surrounding A₁AR and A_2AAR are perhaps the most enticing because of their concentration and affinity; however, as a consequence of distressing conditions, both A_2BAR and A₃AR levels might accumulate. This review focuses on the biological features of each adenosine receptor as the basis of ligand production and describes clinical studies of adenosine receptor-associated pharmaceuticals in human diseases.

Keywords: G protein-coupled receptors; adenosine; adenosine receptors; agonists; allosteric molecules; antagonists.

Figure 1

Production, transport and metabolism of adenosine. Intracellular adenosine is produced via dephosphorylation from the main source, AMP, via both cN I and cN-II and hydrolysis of S-adenosyl-homocysteine through the enzyme S-adenosyl-L-homocysteine hydrolase. The extracellular formation of adenosine is the result of enzymatic cascades consisting of ATP transport, hydrolysis of ATP and ADP by CD39 to form AMP, and dephosphorylation of AMP by CD73. Extracellular adenosine binds adenosine receptors (A₁AR, A_2AAR, A_2BAR, and A₃AR) on the surface of cells. Each AR is a GPCR that transmits the signal from adenosine by activating cAMP.

Figure 2

Schematic representation of adenosine receptors in immune cells. Adenosine receptors carry out the proinflammatory and anti-inflammatory effects of adenosine through predominant immune cells: macrophages, neutrophils, mast cells, lymphocytes, and dendritic cells.