Methylxanthines are alkaloids that can be found in high concentrations in tea, coffee, and chocolate. Theophylline, theobromine, and caffeine are the most popular. They can be found in different concentrations in coffee, chocolate, and tea. Methylxanthines are a unique class of drug that are derived from the purine base xanthine. Xanthine is produced naturally by both plants and animals. The methylxanthines, theophylline, and dyphylline are used in the treatment of airways obstruction caused by conditions such as asthma, chronic bronchitis, or emphysema. Experts are not sure exactly how methylxanthines work, but research has shown they inhibit the enzyme phosphodiesterase, antagonize adenosine receptors, and at lower dosages, their effects on histone deacetylase activity are believed to contribute to their immunomodulatory effects.1

Adenosine (A2A) receptor and its function2

Adenosine is a neuromodulator that is responsible for motor function, mood, memory, and learning. Its main purpose is the coordination of responses to different neurotransmitters. Adenosine plays many important roles in biological systems, for example in the central nervous-, cardiovascular, hepatic, renal and respiratory system. Adenosine plays a role in inflammatory response. Adenosine is released subsequent an inflammation and it prevents tissue damage by reducing inflammation.

A2A receptors are G-protein coupled receptor (GPCR) that increases cyclic adenosine monophosphate (cAMP). These receptors are mainly expressed in the brain. After almost a century of receptor research, the adenosine A2A receptor has been selected as a possible research target for various medical conditions. Antagonists of the receptor have been researched, especially as an enhancer for the therapeutic effects of L-DOPA in Parkinson’s treatment.

Certain evidence points to adenosine A2A receptor antagonism functioning in a neuroprotective manner in the brain. This effect has been noted for both non-selective and selective adenosine A2A receptor antagonists. This neuroprotective function is the manner in which A2A receptor antagonists might help to prevent diseases such as Alzheimer’s, Parkinson’s and Multiple sclerosis. It is still not entirely understood how this neuroprotective action comes about. It has however been hypothesized, that the attenuation of overactive glutamate overflow and reduction of oxidative stress might be the reason for it.

A2A receptor antagonists also appear to function against Parkinson’s disease by modulating GABA release, and by decreasing dopamine-c-Fos activation in the striatopallidal pathway. They are also able to potentiate D2 receptor control of glutamatergic transmission presynaptically – a process which is dysfunctional in Parkinson’s disease.

Structure activity relationship (SAR) of drugs acting on Adenosine (A2A) receptor3,4

Establishing the relationship between structure and efficacy for ligands of adenosine receptors has proven to be a challenge. To be able to characterize the function of adenosine A2 receptors, potent and selective A2-receptor antagonists were required. Various chemical scaffolds of different SAR properties have been reported that show dramatic differences in activity once certain modifications are made.

To achieve high affinity at adenosine receptors, certain criteria must be fulfilled. Adenosine receptor antagonists, in general, are:

  1. Flat
  2. Aromaticor π-electron rich
  3. Nitrogen-containing heterocycles, which are often 6:5 fused.

Substituting hydrophobic groups (such as CH3 or other alkyl chains) on to the compound has the potential to enhance affinity to the receptor, while adding hydrophilic groups (such as N, S, O or OH) is usually suboptimal. This leads to most of the antagonists of the highest affinity being largely insoluble in water. A2A agonists usually have a sugar moiety, which A2A antagonists in general lack. They do, however, usually have a mono-, bi- or tricyclic structure which looks much the same as adenine, the main constituent of adenosine. A2A antagonists have been classified as xanthines and non-xanthines. Caffeine and theophylline (found in coffee and tea, respectively) are examples of well-known xanthines, which act as nonselective A2A antagonists. Both substances act as stimulants, and these properties can be associated with their blockade of the adenosine A2A receptor – for which they have an affinity in the micromolar range.

Core structure of xanthine based adenosine A2A antagonists
These are two examples of core structures of monocyclic non xanthine based A2A adenosine antagonists. There can be different numbers of N in the core cycle and R can be, for example: S, O, NR, NH2 and more.
These are two examples of core structures of bicyclic non-xanthine based A2A adenosine antagonists. There can be different numbers of N in the core cycles and R can be, for example: S, O, NR, NH2 and more.
These are two examples of core structures of tricyclic non xanthine based A2A adenosine antagonists. There can be different numbers of N in the core cycles and R can be, for example: S, O, NR, NH2 and more. The pentagon can also be in the middle of two hexagons.

Several pharmacological limitations are known for xanthine derivatives, such as poor water solubility. Rapid photoisomerization has been observed for the side chain olefin of istradefylline after being exposed to daylight in dilute solutions. Challenges remain for the desirable pharmacologic and physicochemical properties for the discovery of xanthine-based A2A receptor antagonist and the search for alternative non-xanthine-based heterocyclic derivatives has increasingly been the focus of research. The derivatives for non-xanthine-based adenosine A2A receptor antagonists have been classified based on their core structures, as monocyclic, fused bicyclic and fused tricyclic. Currently, several monocyclic core derivatives are being evaluated as potential adenosine A2A receptor antagonists and various fused bicyclic and tricyclic compounds have been identified as such. These antagonists contain an exocyclic amino group and the potency and selectivity have been explored by inserting various substituents onto the heterocyclic templates.

Adenosine A2A receptor antagonism5,6,7

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.

Adenosine A2A receptor locations in the body could help us to understand the possible therapeutic applications in the future. They can be found in the lungs, white blood cells, sympathetic nervous system, striatum, tuberculum olfactorium, coronary, lymphatic, brain and other blood vessels, platelets and kidneys. Most of the therapeutic applications are connected to agonists, but the main focus with antagonists are diseases connected to motor skills, learning and memory, for example Parkinson’s and Alzheimer’s.
Recently, selective A2A receptor antagonists are used in treatment of diseases such as Parkinson’s disease, ischemia, and multiple sclerosis. Selective A2A receptor antagonists are believed to be neuroprotectors for their ability to reduce neuroinflammation.

Parkinson’s disease6

The degradation of dopaminergic neurons in the nigrostriatal pathway is the cause of the motor symptoms of Parkinson’s disease. Several other areas in the brain and other neurotransmitters such as noradrenaline, 5-hydroxytryptamine and acetylcholine are affected in the disease.

Despite the therapies targeting dopamine being effective on Parkinson’s-related motor disturbances, they produce undesirable side effects, such as dyskinesia and hallucinations. These side effects become more severe with continued treatment. Selective A2A receptor antagonists have shown to be beneficial for enhancing the therapeutic effects of L-DOPA and reducing dyskinesia from long-term L-DOPA treatment. Trial results indicated that the viability of A2A receptor antagonists have potential advantages over the current standard treatments for Parkinson’s disease.

Several xanthines and non-xanthines are under development as potential anti-parkinsonism agents, which are selective for A2A receptors. Recently, the A2A receptor antagonist 3-chlorostyrylcaffeine has been reported to be a potent inhibitor of monoamine oxidase B.

An inverse relationship between non-selective adenosine receptor antagonists, the consumption of caffeine and the risk of developing Parkinson’s disease has been indicated from epidemiological studies.

Alzheimers disease7

Alzheimer’s disease (AD) is a neurodegenerative disorder of the central nervous system manifested by cognitive and memory deterioration, a variety of neuropsychiatric symptoms, behavioral disturbances, and progressive impairment of daily life activities.

Current pharmacotherapies are restricted to symptomatic interventions but do not prevent progressive neuronal degeneration.

Epidemiological studies have found an association between coffee (a nonselective adenosine receptor antagonist) consumption and improved cognitive function in AD patients and in the elderly. Long-term administration of caffeine in transgenic animal models showed a reduced amyloid burden in brain with better cognitive performance. Antagonists of adenosine A2A receptors mimic these beneficial effects of caffeine on cognitive function. Neuronal cell cultures with amyloid beta in the presence of an A2A receptor antagonist completely prevented amyloid beta-induced neurotoxicity.

Other diseases5

A2A receptor antagonists may prevent hepatic cirrhosis and also, provide renal protection. The A2A receptor antagonists may be used for treatment of attention deficit hyperactivity disorder (ADHD), because of the receptors ability to regulate neurotransmission in the basal ganglia and cortex, particularly dopaminergic and glutamatergic signaling.

The blockade of A2A receptors has potentially been shown to be protective in several tumor models, through pharmacological inhibition or genetic deletion. Some effects were found to be due to enhanced activity of natural killer cells and also due to enhanced efficacy of anti-PD-1 and anti-CTLA4 antibodies.

In recent studies, the consumption of caffeine-containing beverages and a certain non-xanthine A2A receptor antagonist appear to possibly have some protective effects from Alzheimer’s disease.


Theophylline is a non-selective adenosine antagonist. It is also an anti-asthmatic agent and a demethylated metabolite of caffeine. Small open-label trials suggest that theophylline has anti-parkinsonian benefit, but a double-blind, placebo-controlled trial did not clearly establish relief from symptoms.


Istradefylline, under the brand name Nourianz®, has been approved by the U.S. Food and Drug Administration. Nourianz® are tablets used as an add-on treatment with a Levodopa/Carbidopa treatment.

Istradefylline is a A2A receptor antagonist which increases motor activity and decreases dyskinesia caused by a prolonged administration of L-DOPA and when added to dopamine agonists, it produced synergistic effects.


7-Methylxanthine (7-MX), also known as  heteroxanthine, is an active metabolite of caffeine (1,3,7-trimethylxanthine) and theobromine (3,7-dimethylxanthine). It is a non-selective antagonist of the adenosine receptors. The compound may slow the progression of myopia (nearsightedness) with its primary action on adenosine 2A(A2A) receptor. It is under investigation for this purpose in children with myopia.

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