Pharmacology of Adenosine Receptors: Recent Advancements

Abstract

Adenosine receptors (ARs) are widely acknowledged pharmacological targets yet are still underutilized in clinical practice. Their ubiquitous distribution in almost all cells and tissues of the body makes them, on the one hand, excellent candidates for numerous diseases, and on the other hand, intrinsically challenging to exploit selectively and in a site-specific manner. This review endeavors to comprehensively depict the substantial advancements witnessed in recent years concerning the development of drugs that modulate ARs. Through preclinical and clinical research, it has become evident that the modulation of ARs holds promise for the treatment of numerous diseases, including central nervous system disorders, cardiovascular and metabolic conditions, inflammatory and autoimmune diseases, and cancer. The latest studies discussed herein shed light on novel mechanisms through which ARs exert control over pathophysiological states. They also introduce new ligands and innovative strategies for receptor activation, presenting compelling evidence of efficacy along with the implicated signaling pathways. Collectively, these emerging insights underscore a promising trajectory toward harnessing the therapeutic potential of these multifaceted targets.

Adenosine A3 Receptor: From Molecular Signaling to Therapeutic Strategies for Heart Diseases

“…A 3 AR is a cell surface receptor belonging to the family of G protein-coupled receptors (GPCRs). Upon binding to its agonist, A 3 AR can trigger both G protein-dependent and independent signaling pathways, which vary by cell type; these pathways are associated with anticancer, anti-inflammatory, and cardioprotective effects (reviewed in [ 36 , 37 ]). A 3 AR signaling is characterized by its interaction with both G i and G q proteins.…”

“…A 3 AR signaling is characterized by its interaction with both G i and G q proteins. This dual coupling enables A 3 AR to mediate a diverse range of biological responses depending on the type of G protein activated (reviewed in [ 36 , 37 ]). Notably, A 3 AR demonstrates a significant association with the G i protein, resulting in the inhibition of cyclic adenosine monophosphate (cAMP) production and thereby activating the mitogen-activated protein kinase (MAPK) pathway, including ERK1/2 and p38 [ 38 ] ( Figure 1 ).…”

“…Following A 3 AR coupling with G i protein, the inhibition of cAMP formation indirectly reduces glycogen synthase kinase-3 beta (GSK-3β) activity, leading to an increase in the phosphorylation of β-catenin. This prevents β-catenin from translocating to the nucleus, resulting in the decreased expression of various target genes that regulate cell cycle progression, such as cyclin D1 and c-myc, ultimately inhibiting cell growth (reviewed in [ 13 , 15 , 37 ]). Of note, the activation of G i protein-dependent signaling can have detrimental effects on the heart.…”

“…This has led to a focused effort to explore the potential of selective A 3 AR agonists for protecting the heart. Various A 3 AR-specific agonists, including IB-MECA, Cl-IB-MECA, CP-532903, and CP-608039, have been examined for their effectiveness in treating a range of heart conditions, such as I/R injury and cardiac remodeling [ 5 , 15 , 37 ]. The cardioprotective effects of A 3 AR agonists have been studied across different animal models, including rodents and rabbits, as shown in Table 1 .…”

Pyrazolo-triazolo-pyrimidine Scaffold as a Molecular Passepartout for the Pan-Recognition of Human Adenosine Receptors

“…The consequences of these interactions are a reduction, in the case of A 1 and A 3 , or an increase, in the case of A 2A and A 2B , in the cAMP levels as the second messenger. In addition, all four subtypes may positively couple to phospholipase C via different Gprotein subunits [1][2][3][4]. It has also been demonstrated that adenosine receptors can activate different signal pathways not related to G proteins, like the β-arrestin one, which induces different responses with respect to the G-protein signals [3].…”