Target Background

The adenosine receptors (ARs) are a family of class A G-protein-coupled receptors (GPCRs) that mediate the physiological and pharmacological actions of the endogenous nucleoside adenosine. Four subtypes have been identified: A₁, A₂A, A₂B, and A₃. These receptors are widely distributed throughout the body, with subtype-specific patterns in the central nervous system, cardiovascular system, lungs, kidneys, and immune cells. Their broad distribution underlies diverse roles in neuromodulation, cardiac rhythm regulation, vasodilation, inflammation, and immune responses.

Adenosine receptors couple to different G-proteins depending on subtype. A₁ and A₃ receptors predominantly couple to Gi/o proteins, leading to inhibition of adenylate cyclase and reduced intracellular cAMP, whereas A₂A and A₂B receptors couple to Gs proteins, stimulating adenylate cyclase and elevating cAMP. Additional pathways involve modulation of ion channels, MAPK signaling, and phospholipase C, contributing to tissue- and context-dependent effects. For example, A₁ receptor activation in the CNS suppresses excitatory neurotransmission, while A₂A receptor activity in the striatum modulates dopaminergic signaling and motor control.

Pharmacologically, adenosine receptors are important therapeutic targets across multiple disease areas. A₂A receptor antagonists have been approved for Parkinson’s disease (e.g., istradefylline), while A₁ receptor agonists and antagonists are under exploration for cardiac arrhythmias and chronic kidney disease. A₂B and A₃ receptors have been implicated in asthma, pulmonary fibrosis, cancer, and inflammatory disorders, with selective ligands progressing in clinical development. With their central role in regulating neurotransmission, cardiovascular function, and immune homeostasis, adenosine receptors represent a versatile and expanding area of drug discovery.