Adenosine receptor

The adenosine receptors (or P1 receptors[1]) are a class of purinergic receptors, G protein-coupled receptors with adenosine as endogenous ligand.[2]



In humans, there are four adenosine receptors. Each is encoded by a separate gene and has different functions, although with some overlap.[3] For instance, both A1 receptors and A2A play roles in the heart, regulating myocardial oxygen consumption and coronary blood flow, while the A2A receptor also has broader anti-inflammatory effects throughout the body.[4] These two receptors also have important roles in the brain,[5] regulating the release of other neurotransmitters such as dopamine and glutamate,[6][7][8] while the A2B and A3 receptors are located mainly peripherally and are involved in processes such as inflammation and immune responses.

Most older compounds acting on adenosine receptors are nonselective, with the endogenous agonist adenosine being used in hospitals as treatment for severe tachycardia (rapid heart beat),[9] and acting directly to slow the heart through action on all four adenosine receptors in heart tissue,[10] as well as producing a sedative effect through action on A1 and A2A receptors in the brain. Xanthine derivatives such as caffeine and theophylline act as non-selective antagonists at A1 and A2A receptors in both heart and brain and so have the opposite effect to adenosine, producing a stimulant effect and rapid heart rate.[11] These compounds also act as phosphodiesterase inhibitors, which produces additional anti-inflammatory effects, and makes them medically useful for the treatment of conditions such as asthma, but less suitable for use in scientific research.[12]

Newer adenosine receptor agonists and antagonists are much more potent and subtype-selective, and have allowed extensive research into the effects of blocking or stimulating the individual adenosine receptor subtypes, which is now resulting in a new generation of more selective drugs with many potential medical uses. Some of these compounds are still derived from adenosine or from the xanthine family, but researchers in this area have also discovered many selective adenosine receptor ligands that are entirely structurally distinct, giving a wide range of possible directions for future research.[13][14]

Comparison of subtypes

Adenosine receptors
Receptor Gene Mechanism [15] Effects Agonists Antagonists
A1 ADORA1 Gi/ocAMP↑/↓
  • Inhibition
    • ↓ vesicle release
A2B ADORA2B GscAMP↑ ,also recently discovered A2B has Gq→DAG and IP3→Release calcium→active calmodulin→activate myosin light chain kinase→phosphrylate myosin light chain→myosin light chain plus actin→bronchoconstriction. *bronchospasm
  • 5'-N-ethylcarboxamidoadenosine
  • BAY 60–6583
  • LUF-5835
  • LUF-5845
  • theophylline
  • CVT-6883
  • MRS-1706
  • MRS-1754
  • PSB-603
  • PSB-0788
  • PSB-1115
A3 ADORA3 Gi/o → ↓cAMP
  • cardioprotective in cardiac ischemia
  • inhibition of neutrophil degranulation
  • 2-(1-Hexynyl)-N-methyladenosine
  • CF-101 (IB-MECA)
  • 2-Cl-IB-MECA
  • CP-532,903
  • MRS-3558
  • theophylline
  • MRS-1191
  • MRS-1220
  • MRS-1334
  • MRS-1523
  • MRS-3777
  • MRE3008F20
  • PSB-10
  • PSB-11
  • VUF-5574

A1 adenosine receptor

The adenosine A1 receptor has been found to be ubiquitous throughout the entire body.


This receptor has an inhibitory function on most of the tissues in which it is expressed. In the brain, it slows metabolic activity by a combination of actions. Presynaptically, it reduces synaptic vesicle release while post synaptically it has been found to stabilize the magnesium on the NMDA receptor.

Antagonism and agonism

Specific A1 antagonists include 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), and Cyclopentyltheophylline‎ (CPT) or 8-cyclopentyl-1,3-dipropylxanthine‎ (CPX), while specific agonists include 2-chloro-N(6)-cyclopentyladenosine (CCPA).

In the heart

The A1, together with A2A receptors of endogenous adenosine play a role in regulating myocardial oxygen consumption and coronary blood flow. Stimulation of the A1 receptor has a myocardial depressant effect by decreasing the conduction of electrical impulses and suppressing pacemaker cell function, resulting in a decrease in heart rate. This makes adenosine a useful medication for treating and diagnosing tachyarrhythmias, or excessively fast heart rates. This effect on the A1 receptor also explains why there is a brief moment of cardiac standstill when adenosine is administered as a rapid IV push during cardiac resuscitation. The rapid infusion causes a momentary myocardial stunning effect.

In normal physiological states, this serves as protective mechanisms. However, in altered cardiac function, such as hypoperfusion caused by hypotension, heart attack or cardiac arrest caused by nonperfusing bradycardias, adenosine has a negative effect on physiological functioning by preventing necessary compensatory increases in heart rate and blood pressure that attempt to maintain cerebral perfusion.

In neonatal medicine

Adenosine antagonists are widely used in neonatal medicine;

Because a reduction in A1 expression appears to prevent hypoxia-induced ventriculomegaly and loss of white matter and therefore raise the possibility that pharmacological blockade of A1 may have clinical utility.

Theophylline and caffeine are nonselective adenosine antagonists that are used to stimulate respiration in premature infants.

A2A adenosine receptor

As with the A1, the A2A receptors are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow.


The activity of A2A adenosine receptor, a G-protein coupled receptor family member, is mediated by G proteins that activate adenylyl cyclase. It is abundant in basal ganglia, vasculature and platelets and it is a major target of caffeine.[16]


The A2A receptor is responsible for regulating myocardial blood flow by vasodilating the coronary arteries, which increases blood flow to the myocardium, but may lead to hypotension. Just as in A1 receptors, this normally serves as a protective mechanism, but may be destructive in altered cardiac function.

Agonists and antagonists

Specific antagonists include istradefylline (KW-6002) and SCH-58261, while specific agonists include CGS-21680 and ATL-146e.[17]

A2B adenosine receptor

This integral membrane protein stimulates adenylate cyclase activity in the presence of adenosine. This protein also interacts with netrin-1, which is involved in axon elongation.

A3 adenosine receptor

It has been shown in studies to inhibit some specific signal pathways of adenosine. It allows for the inhibition of growth in human melanoma cells. Specific antagonists include MRS1191, MRS1523 and MRE3008F20, while specific agonists include Cl-IB-MECA and MRS3558.[17]


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  6. ^ Fuxe K, Ferré S, Genedani S, Franco R, Agnati LF (September 2007). "Adenosine receptor-dopamine receptor interactions in the basal ganglia and their relevance for brain function". Physiology & Behavior 92 (1-2): 210–7. doi:10.1016/j.physbeh.2007.05.034. PMID 17572452. 
  7. ^ Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferré S (December 2007). "Adenosine A2A receptors and basal ganglia physiology". Progress in Neurobiology 83 (5): 277–92. doi:10.1016/j.pneurobio.2007.05.001. PMC 2148496. PMID 17646043. 
  8. ^ Cunha RA, Ferré S, Vaugeois JM, Chen JF (2008). "Potential therapeutic interest of adenosine A2A receptors in psychiatric disorders". Current Pharmaceutical Design 14 (15): 1512–24. doi:10.2174/138161208784480090. PMC 2423946. PMID 18537674. 
  9. ^ Peart JN, Headrick JP (May 2007). "Adenosinergic cardioprotection: multiple receptors, multiple pathways". Pharmacology & Therapeutics 114 (2): 208–21. doi:10.1016/j.pharmthera.2007.02.004. PMID 17408751. 
  10. ^ Cohen MV, Downey JM (May 2008). "Adenosine: trigger and mediator of cardioprotection". Basic Research in Cardiology 103 (3): 203–15. doi:10.1007/s00395-007-0687-7. PMID 17999026. 
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  12. ^ Osadchii OE (June 2007). "Myocardial phosphodiesterases and regulation of cardiac contractility in health and cardiac disease". Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy 21 (3): 171–94. doi:10.1007/s10557-007-6014-6. PMID 17373584. 
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  14. ^ Cristalli G, Lambertucci C, Marucci G, Volpini R, Dal Ben D (2008). "A2A adenosine receptor and its modulators: overview on a druggable GPCR and on structure-activity relationship analysis and binding requirements of agonists and antagonists". Current Pharmaceutical Design 14 (15): 1525–52. doi:10.2174/138161208784480081. PMID 18537675. 
  15. ^ Unless else specified in boxes, then ref is:senselab
  16. ^ "Entrez Gene: ADORA2A adenosine A2A receptor". 
  17. ^ a b Jacobson KA, Gao ZG (2006). "Adenosine receptors as therapeutic targets". Nature reviews. Drug discovery 5 (3): 247–64. doi:10.1038/nrd1983. PMID 16518376. 

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