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.

Keywords: A1; A2A; A2B; A3; adenosine; adenosine receptors; therapeutic potential.

Figure 1

Overview of adenosine metabolism and AR intracellular signaling. Extracellularly, adenosine (ADO) is primarily derived from adenosine monophosphate (AMP) via the catalytic action of ecto-5′-nucleotidase (CD73). Multiple enzymatic pathways, including nucleoside triphosphate diphosphohydrolase-1 (NTPDase1 or CD39), NTPDase2 and NTPDase3, nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1), and adenylate kinase-1 (AK1), contribute to the generation of AMP from ATP. Adenosine transport across the cell membrane is facilitated by equilibrative nucleoside transporters (ENTs). Intracellularly, AMP is converted to adenosine by cytosolic 5′-nucleotidase (5′NT), and the reverse reaction is mediated by adenosine kinase (ADK). Additionally, ATP to ADP and ADP to AMP interconversions are catalyzed by AK-1 and nucleotide diphosphokinase (NDPK), respectively. Adenosine can also be generated from S-adenosylhomocysteine (SAH) through the enzymatic action of SAH hydrolase (SAHH). Its enzymatic degradation occurs via adenosine deaminase (ADA), which converts adenosine to inosine (INO). On the signaling front, A_2A and A_2B ARs activate adenylyl cyclase (AC) through Gs protein coupling, stimulating the conversion of ATP to cyclic AMP (cAMP). Conversely, A₁ and A₃ ARs inhibit AC via Gi protein coupling. The primary downstream effectors of cAMP are cAMP-dependent protein kinase (PKA) and exchange protein directly activated by cAMP (EPAC). PKA primarily regulates transcription through phosphorylation of the cAMP response element-binding protein (CREB). Protein kinase B (PKB) and mitogen-activated protein kinases (MAPK) are common substrates for PKA. Additionally, A_2B and A₃ ARs can activate Gq proteins, thereby stimulating phospholipase C (PLC) and subsequently leading to the formation of diacylglycerol (DAG) and inositol triphosphate (IP3). These molecules activate protein kinase C and elevate intracellular Ca²⁺ levels, respectively. A₃ARs also regulate the phosphatidylinositol 3-kinase (PI3K)/PKB axis via Gq proteins. A₁AR activation modulates ion channels, thus inhibiting Ca²⁺ channels and activating K⁺ channels.

Figure 2

Therapeutic potential of adenosine receptors. The physiological effects of the receptors are in light blue, the pharmacological actions of ligands suitable for treatment are in light green, and the pathologies in which the ligands can be utilized are in pink.