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Theadenosine receptors (orP1 receptors^[1]) are a class ofpurinergicG protein-coupled receptors withadenosine as theendogenousligand.^[2] There are four known types of adenosine receptors in humans:A₁,A_2A,A_2B andA₃; each is encoded by a differentgene.

The adenosine receptors are commonly known for their antagonistscaffeine,theophylline, andtheobromine, whose action on the receptors produces the stimulating effects ofcoffee,tea andchocolate.

Each type of adenosine receptor has different functions, although with some overlap.^[3] For instance, both A₁ receptors and A_2A play roles in the heart, regulatingmyocardial oxygen consumption andcoronary blood flow, while the A_2A 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 otherneurotransmitters such asdopamine andglutamate,^[6][7][8] while the A_2B 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 agonistadenosine being used in hospitals as treatment for severetachycardia (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 asedative effect through action on A₁ and A_2A receptors in the brain.Xanthine derivatives such ascaffeine andtheophylline act as non-selectiveantagonists at A₁ and A_2A receptors in both heart and brain and so have the opposite effect to adenosine, producing astimulant effect and rapid heart rate.^[11] These compounds also act asphosphodiesterase inhibitors, which produces additionalanti-inflammatory effects, and makes them medically useful for the treatment of conditions such asasthma, 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]

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 reducessynaptic vesicle release while post synaptically it has been found to stabilize themagnesium on theNMDA receptor^source?.

Specific A₁antagonists include8-cyclopentyl-1,3-dipropyl xanthine (DPCPX), andcyclopentyltheophylline (CPT) or 8-cyclopentyl-1,3-dipropylxanthine (CPX), while specific agonists include 2-chloro-N(6)-cyclopentyladenosine (CCPA).

Tecadenoson is an effective A₁ adenosine agonist, as isselodenoson.

The A₁, together with A_2A receptors of endogenous adenosine play a role in regulatingmyocardial oxygen consumption and coronary blood flow. Stimulation of the A₁ receptor has a myocardial depressant effect by decreasing the conduction of electrical impulses and suppressingpacemaker cell function, resulting in a decrease inheart rate. This makes adenosine a useful medication for treating and diagnosingtachyarrhythmias, 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 rapidIV push duringcardiac resuscitation. The rapid infusion causes a momentary myocardial stunning effect.

In normal physiological states, this serves as a protective mechanism. However, in altered cardiac function, such ashypoperfusion caused byhypotension,heart attack orcardiac arrest caused bynonperfusing bradycardias (e.g.,ventricular fibrillation orpulseless ventricular tachycardia^[16]), 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.

Adenosine antagonists are widely used inneonatal medicine;

A reduction in A₁ expression appears to prevent hypoxia-inducedventriculomegaly and loss of white matter, which raises 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.

Adenosine receptors play a key role in the homeostasis of bone. The A₁ receptor has been shown to stimulateosteoclast differentiation and function.^[17] Studies have found that blockade of the A₁ Receptor suppresses the osteoclast function, leading to increased bone density.^[18]

As with the A₁, the A_2A receptors are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow.

The activity of A_2A adenosine receptor, a G-protein coupled receptor family member, is mediated by G proteins that activateadenylyl cyclase. It is abundant in basal ganglia, vasculature and platelets and it is a major target of caffeine.^[19]

The A_2A receptor is responsible for regulating myocardial blood flow byvasodilating thecoronary arteries, which increases blood flow to themyocardium, 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.

Specific antagonists includeistradefylline (KW-6002) andSCH-58261, while specific agonists includeCGS-21680 and ATL-146e.^[20]

The role of A2A receptor opposes that of A1 in that it inhibits osteoclast differentiation and activatesosteoblasts.^[21] Studies have shown it to be effective in decreasing inflammatory osteolysis in inflamed bone.^[22] This role could potentiate new therapeutic treatment in aid of bone regeneration and increasing bone volume.

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

Similarly to A2A receptor, the A2B receptor promotes osteoblast differentiation.^[23] The osteoblast cell is derived from the Mesenchymal Stem Cell (MSC) which can also differentiate into a chondrocyte.^[24] The cell signalling involved in the stimulation of the A2B receptor directs the route of differentiation to osteoblast, rather than chondrocyte via the Runx2 gene expression.^[24] Potential therapeutic application in aiding bone degenerative diseases, age related changes as well as injury repair.

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 includeMRS1191,MRS1523 andMRE3008F20, while specific agonists includeCl-IB-MECA and MRS3558.^[20]

The role of A3 receptor is less defined in this field. Studies have shown that it plays a role in the downregulation ofosteoclasts.^[25] Its function in regards to osteoblasts remains ambiguous.

• "Adenosine Receptors".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2016-10-24. Retrieved2006-07-20.
• Adenosine+Receptors at the U.S. National Library of MedicineMedical Subject Headings (MeSH)

• G protein-coupled receptors
• Adenosine receptors

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