Molecular Classification
G protein-coupled receptor (GPCR), Receptor, Purinergic receptor (P1 class)
Other Names
Adenosine A1 receptor, A1 adenosine receptor, Adenosine A2B receptor, A2B adenosine receptor, Adenosine A3 receptor, A3 adenosine receptor, P1 receptors
Disease Roles
Cardiovascular disease (A1R, A2BR)Inflammation (A2BR, A3R)Diabetes/metabolic syndrome (A1R, A2BR)

Adenosine receptors A1, A2B, and A3 Overview

Adenosine receptors A1, A2B, and A3 are members of the purinergic P1 GPCR family, widely expressed in human tissues where they mediate the physiological effects of adenosine. Each subtype couples to distinct G proteins, producing different biochemical effects: A1 and A3 generally inhibit adenylyl cyclase (via Gi proteins) to decrease cAMP, while A2BR primarily stimulates cAMP production (via Gs proteins)[4][2][3][1]. The A1 receptor is mainly found in the central nervous system and heart, where it promotes neuroprotection and reduces heart rate. The A2B receptor is prominent in peripheral tissues such as the lung and vasculature, modulating inflammation and vascular tone. The A3 receptor is expressed in immune tissues and cancer cells, and is involved in immune modulation and cell death pathways[2][3][1][4]. Therapeutic modulation of these receptors is being pursued in a variety of diseases, but achieving clinical success depends on developing ligands with high receptor subtype selectivity and minimizing off-target/safety issues[3][2][4][1].

Mechanism of Action

Agonists stimulate the receptor, modulating intracellular cAMP and downstream kinase signaling pathways (e.g., ERK, JNK, p38), protein kinase C, and calcium flux; the precise effect is subtype-dependent. Antagonists block the receptor, preventing endogenous adenosine from exerting its effects—commonly resulting in stimulant or anti-inflammatory outcomes (caffeine and theophylline block A1R and A2A).

Biological Functions

Signal transduction
Neuroprotection (esp. A1R)
Modulation of neurotransmitter release
Regulation of cardiac function and coronary blood flow (A1R, A2BR)
Regulation of inflammation and immune response (A2BR, A3R)
Modulation of cell proliferation and apoptosis (A3R, A2BR, context dependent)
Regulation of metabolism and glucose/lipid homeostasis (A1R)

Disease Associations

Cardiovascular disease (A1R, A2BR)
Inflammation (A2BR, A3R)
Diabetes/metabolic syndrome (A1R, A2BR)
Cancer (A2BR, A3R)
Neurodegenerative disease (A1R, A3R)
Asthma (especially A2BR)
Autoimmune disease (A3R)

Safety Considerations

  • Low subtype selectivity of many ligands (leads to off-target effects)
  • Cardiac depression or bradycardia (esp. A1R agonists)
  • CNS or psychiatric effects (antagonists such as caffeine)
  • Species differences in receptor pharmacology/response
  • Potential immunosuppression or excessive inflammatory effects with some receptor subtype modulators

Interacting Drugs

Agonists: Adenosine (endogenous)
Agonists: NECA (nonselective)
Agonists: BAY60-6583 (A2BR agonist)
Agonists: CVT-3619 (A1R agonist)
Agonists: Cl-IB-MECA (A3R agonist)
Antagonists: Caffeine
Antagonists: Theophylline
Antagonists: Theobromine (nonselective or A1/A2A selective)
Antagonists: PSB-603 (A2BR antagonist)
Antagonists: Istradefylline (A2A selective, but related)
Adenosine itself (used therapeutically for supraventricular tachycardia; nonselective)

Associated Biomarkers

Biomarker
The expression of each subtype in target organs/tissues (e.g., A1R in heart, brain; A2BR in lung and vasculature; A3R in immune and cancer cells) may act as a patient selection or efficacy biomarker for investigational drugs, but no single companion biomarker is universally established.