Adenosine receptor

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The adenosine receptors (or P1 receptors [1] ) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. [2] There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a different gene.

Contents

The adenosine receptors are commonly known for their antagonists caffeine, theophylline, and theobromine, whose action on the receptors produces the stimulating effects of coffee, tea and chocolate.

Pharmacology

Caffeine keeps you awake by blocking adenosine receptors. 10 caffeine knowing-neurons.jpg
Caffeine keeps you awake by blocking adenosine receptors.

Each type of adenosine receptor 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]

Subtypes

Comparison

Adenosine receptors
ReceptorGeneMechanism [15] EffectsAgonistsAntagonists
A1 ADORA1 Gi/o → cAMP↑/↓
A2A ADORA2A Gs → cAMP↑
A2B ADORA2B Gs → cAMP↑

Also recently discovered A2B has Gq → DAG and IP3 → Release calcium → activate calmodulin → activate myosin light chain kinase → phosphorylate myosin light chain → myosin light chain plus actin → bronchoconstriction[ citation needed ]

A3 ADORA3 Gi/o → ↓cAMP

A1 adenosine receptor

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

Mechanism

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 source?.

Antagonism and agonism

Specific A1 antagonists include 8-cyclopentyl-1,3-dipropyl xanthine (DPCPX), and cyclopentyltheophylline (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 is selodenoson.

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 a protective mechanism. However, in altered cardiac function, such as hypoperfusion caused by hypotension, heart attack or cardiac arrest caused by nonperfusing bradycardias (e.g., ventricular fibrillation or pulseless 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.

In neonatal medicine

Adenosine antagonists are widely used in neonatal medicine;

A reduction in A1 expression appears to prevent hypoxia-induced ventriculomegaly 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.

Bone homeostasis

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

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.

Mechanism

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. [19]

Function

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. [20]

Bone homeostasis

The role of A2A receptor opposes that of A1 in that it inhibits osteoclast differentiation and activates osteoblasts. [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.

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.

Bone homeostasis

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.

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. [20]

Bone homeostasis

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

Ligand affinities

Adenosine receptor agonists

Binding affinities (Ki, nM) of notable adenosine receptor agonists [26] [27]
Compound A1 A2A A2B A3 Selectivity
Adenosine ~100 (h)
73 (r)		310 (h)
150 (r)		15,000 (h)
5100 (r)		290 (h)
6500 (r)		Non-selective
2-Chloroadenosine 6.7 (r)76 (r)24,000 (h)1890 (r)A1-selective
CV-1808 400 (r)100 (r)NDNDND
NECA 14 (h)
5.1 (r)		20 (h)
9.7 (r)		140 (h)
1890 (h)
1900 (m)		25 (h)
113 (r)		Non-selective
CGS-21680 289 (h)
1800 (r)
120 (rb)		27 (h)
19 (r)		>10,000 (h)
>10,000 (r)		67 (h)
584 (r)
673 (rb)		A2A-selective
HENECA 60 (h)6.4 (h)61002.4 (h)Non-selective
BAY 60-6583 >10,000 (h)>10,000 (h)3–10 (h)
330 (m)
750 (d)
340 (rb)		>10,000 (h)A2B-selective
Notes: Values are in nanomolar (nM) units. The smaller the value, the more avidly the compound binds to the site. The parentheses after values indicate the species: h = human, r = rat, m = mouse, rb = rabbit, d = dog.

Adenosine receptor antagonists

Binding affinities (Ki, nM) of notable adenosine receptor antagonists [26] [28]
Compound A1 A2A A2B A3 Selectivity
Caffeine 10,700 (h)
44,900 (h)
41,000 (r)
44,000 (r)
47,000 (gp)
44,000 (c)		23,400 (h)
9560 (h)
45,000 (r)
32,500 (r)
48,000 (r)		33,800 (h)
10,400 (h)
20,500 (h)
30,000 (r)
13,000 (m)		13,300 (h)
>100,000 (r)		Non-selective
Theophylline 6770 (h)
14,000 (r)
8740 (r)
7060 (gp)
4710 (rb)
9050 (s)
6330 (c)		1710 (h)
6700 (h)
22,000 (r)
25300 (r)		9070 (h)
74,000 (h)
15,100 (r)
5630 (m)
11,000 (gp)
17,700 (rb)
38,700 (d)		22,300 (h)
86,400 (h)
>100,000 (r)
85,000 (r)
>100,000 (d)		Non-selective
Theobromine 105,000 (r)
83,400 (r)		>250,000 (r)
187,000 (r)		130,000 (h)>100,000 (r)Non-selective
Paraxanthine 21,000 (r)32,000 (r)4,500 (h)>100,000 (r)Non-selective
3-Chlorostyrylcaffeine (CSC)28,000 (r)54 (r)8200>10,000 (r)A2A-selective
MSX-2 900 (r)
2500 (h)		8.04 (r)
5.38 (h)
14.5 (h)		>10,000 (h)>10,000 (h)A2A-selective
Istradefylline (KW-6002)841 (h)
230 (r)		12 (h)
91.2 (h)
2.2 (r)
4.46 (r)		>10,000 (h)4470 (h)A2A-selective
CGS-15943 3.5 (h)1.2 (h)32.4 (h)35 (h)Non-selective
SCH-58261 725 (h)5.0 (h)1110 (h)1200 (h)A2A-selective
ZM-241385 2550.850>10,000A2A-selective
Preladenant (SCH-420814)>1000 (h)0.9 (h)>1000 (h)>1000 (h)A2A-selective
Notes: Values are in nanomolar (nM) units. The smaller the value, the more avidly the compound binds to the site. The parentheses after values indicate the species: h = human, r = rat, m = mouse, gp = guinea pig, rb = rabbit, c = calf or cow, s = sheep.

Related Research Articles

<span class="mw-page-title-main">Phosphodiesterase inhibitor</span> Drug

A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.

<span class="mw-page-title-main">Xanthine</span> Chemical compound

Xanthine is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffeine, theophylline, and theobromine.

<span class="mw-page-title-main">Adenosine</span> Chemical compound

Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building blocks of RNA (and its derivative deoxyadenosine is a building block of DNA), which are essential for all life on Earth. Its derivatives include the energy carriers adenosine mono-, di-, and triphosphate, also known as AMP/ADP/ATP. Cyclic adenosine monophosphate (cAMP) is pervasive in signal transduction. Adenosine is used as an intravenous medication for some cardiac arrhythmias.

<span class="mw-page-title-main">Aminophylline</span> Chemical compound

Aminophylline is a compound of the bronchodilator theophylline with ethylenediamine in 2:1 ratio. The ethylenediamine improves solubility, and the aminophylline is usually found as a dihydrate.

<span class="mw-page-title-main">Paraxanthine</span> Chemical compound

Paraxanthine, also known as 1,7-dimethylxanthine, is a metabolite of theophylline and theobromine, two well-known stimulants found in coffee, tea, and chocolate mainly in the form of caffeine. It is a member of the xanthine family of alkaloids, which includes theophylline, theobromine and caffeine.

Adenosine A<sub>1</sub> receptor Cell surface receptor found in humans

The adenosine A1 receptor (A1AR) is one member of the adenosine receptor group of G protein-coupled receptors with adenosine as endogenous ligand.

Adenosine A<sub>2A</sub> receptor Cell surface receptor found in humans

The adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor, and also denotes the human gene encoding it.

Adenosine A<sub>3</sub> receptor Cell surface receptor found in humans

The adenosine A3 receptor, also known as ADORA3, is an adenosine receptor, but also denotes the human gene encoding it.

Adenosine A<sub>2B</sub> receptor Cell surface receptor found in humans

The adenosine A2B receptor, also known as ADORA2B, is a G-protein coupled adenosine receptor, and also denotes the human adenosine A2b receptor gene which encodes it.

<span class="mw-page-title-main">Dipropylcyclopentylxanthine</span> Chemical compound

8-Cyclopentyl-1,3-dipropylxanthine (DPCPX, PD-116,948) is a drug which acts as a potent and selective antagonist for the adenosine A1 receptor. It has high selectivity for A1 over other adenosine receptor subtypes, but as with other xanthine derivatives DPCPX also acts as a phosphodiesterase inhibitor, and is almost as potent as rolipram at inhibiting PDE4. It has been used to study the function of the adenosine A1 receptor in animals, which has been found to be involved in several important functions such as regulation of breathing and activity in various regions of the brain, and DPCPX has also been shown to produce behavioural effects such as increasing the hallucinogen-appropriate responding produced by the 5-HT2A agonist DOI, and the dopamine release induced by MDMA, as well as having interactions with a range of anticonvulsant drugs.

<span class="mw-page-title-main">SCH-58261</span> Chemical compound

SCH-58261 is a drug which acts as a potent and selective antagonist for the adenosine receptor A2A, with more than 50x selectivity for A2A over other adenosine receptors. It has been used to investigate the mechanism of action of caffeine, which is a mixed A1 / A2A antagonist, and has shown that the A2A receptor is primarily responsible for the stimulant and ergogenic effects of caffeine, but blockade of both A1 and A2A receptors is required to accurately replicate caffeine's effects in animals. SCH-58261 has also shown antidepressant, nootropic and neuroprotective effects in a variety of animal models, and has been investigated as a possible treatment for Parkinson's disease.

<span class="mw-page-title-main">PSB-10</span> Chemical compound

PSB-10 is a drug which acts as a selective antagonist for the adenosine A3 receptor (ki value at human A3 receptor is 0.44 nM), with high selectivity over the other three adenosine receptor subtypes (ki values at human A1, A2A and A2B receptors are 4.1, 3.3 and 30 μM). Further pharmacological experiments in a [35S]GTPγS binding assay using hA3-CHO-cells indicated that PSB-10 acts as an inverse agonist (IC50 = 4 nM). It has been shown to produce antiinflammatory effects in animal studies. Simple xanthine derivatives such as caffeine and DPCPX have generally low affinity for the A3 subtype and must be extended by expanding the ring system and adding an aromatic group to give high A3 affinity and selectivity. The affinity towards adenosine A3 subtype was measured against the radioligand PSB-11.

<span class="mw-page-title-main">CGS-15943</span> Chemical compound

CGS-15943 is a drug which acts as a potent and reasonably selective antagonist for the adenosine receptors A1 and A2A, having a Ki of 3.3nM at A2A and 21nM at A1. It was one of the first adenosine receptor antagonists discovered that is not a xanthine derivative, instead being a triazoloquinazoline. Consequently, CGS-15943 has the advantage over most xanthine derivatives that it is not a phosphodiesterase inhibitor, and so has more a specific pharmacological effects profile. It produces similar effects to caffeine in animal studies, though with higher potency.

<span class="mw-page-title-main">Purinergic signalling</span> Signalling complex involving purine nucleosides and their receptors

Purinergic signalling is a form of extracellular signalling mediated by purine nucleotides and nucleosides such as adenosine and ATP. It involves the activation of purinergic receptors in the cell and/or in nearby cells, thereby regulating cellular functions.

An adenosine receptor antagonist is a drug which acts as an antagonist of one or more of the adenosine receptors. The best known are xanthines and their derivatives, but there are also non-xanthine representatives

Caffeine-induced anxiety disorder is a subclass of the DSM-5 diagnosis of substance/medication-induced anxiety disorder.

Adenosine A2A receptor antagonists are a class of drugs that blocks adenosine at the adenosine A2A receptor. Notable adenosine A2A receptor antagonists include caffeine, theophylline and istradefylline.

<span class="mw-page-title-main">MSX-3</span> Selective adenosine A2A receptor antagonist used in scientific research

MSX-3 is a selective adenosine A2A receptor antagonist used in scientific research. Similarly to MSX-4, it is a water-soluble ester prodrug of MSX-2.

<span class="mw-page-title-main">3-Chlorostyrylcaffeine</span> A selective adenosine A2A receptor antagonist and MAO-B inhibitor used in scientific research

3-Chlorostyrylcaffeine (CSC), or 8-(3-chlorostyryl)caffeine (8-CSC), is a potent and selective adenosine A2A receptor antagonist which is used in scientific research.

<span class="mw-page-title-main">MSX-2</span> A selective adenosine A2A receptor antagonist

MSX-2 is a selective adenosine A2A receptor antagonist used in scientific research. It is a xanthine and a derivative of the non-selective adenosine receptor antagonist caffeine.

References

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