Adenosine A2A receptor antagonist

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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. [1]

Contents

Clinical significance

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. [1]

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. [2]

Parkinson's disease

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. [3] The etiology of Parkinson's disease is still uncertain, but it is believed that the progressive degeneration of dopaminergic neurons is connected with chronic neuroinflammation and the key factor in this process is microglia activation. [4]

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. [5]

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. [6]

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. [4] [6]

Other diseases

A2A receptor antagonists may prevent hepatic cirrhosis, and pentoxifylline may inhibit phosphodiesterase and provide renal protection. [6]

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. [7]

The blockade of A2A receptors has potentially 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. [7]

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. [6]

Development

Similar to other G protein-coupled receptors, A2A receptors form both homo- and heterodimers. The presence of heterodimeric complexes has progressed in suggesting new ways to regulate neuronal activity by targeting the A2A receptor. [3]

In spite of the efforts to identify potent compounds, challenges still remain in achieving selectivity, solubility and acceptable pharmacokinetic or pharmacodynamic properties of the potent compounds and for it to progress into the clinic. [5]

It was not until 1981 when the underlying targets involved in the behavioral stimulant properties of methylxanthines (such as caffeine) were recognized. The stimulant properties of caffeine and various analogs were correlated with the blockade of adenosine receptors. It was proposed that the cause of behavioral depression was due to inhibition of cyclic nucleotide phosphodiesterases when taking high doses of caffeine and some xanthine analogs. It was clear that ligands of adenosine receptors and inhibitors for phosphodiesterase were targets for drug development. [6]

In 1992, the therapeutic potential for both agonists and antagonists of the adenosine receptors was highlighted for A2 receptors, and in 2001 the therapeutic potential for adenosine antagonists was highlighted. Broad reviews from 2006 have been focusing on adenosine receptors as therapeutic targets, adenosine receptor antagonists as potential therapeutics, antagonist for A2A-receptors, adenosine receptor ligands as anti-inflammatories and many more. [6]

Several attempts have been made by using virtual screening to identify potent A2A adenosine receptor antagonists. Both docking-based screening using protein structures obtained from homology modeling and experimental determination of crystal structures of the A2A adenosine receptor are used to identify the potent compounds. [8]

Caffeine is a non-selective A2A antagonist. Replacing one or two of the methyl groups with propyl or propargyl increases the selectivity towards the receptor. Caffeine structure.svg
Caffeine is a non-selective A2A antagonist. Replacing one or two of the methyl groups with propyl or propargyl increases the selectivity towards the receptor.

Caffeine

Caffeine is classified as a non-selective adenosine receptor antagonist. Epidemiological and laboratory data are interpreting that consuming caffeine and coffee are linked to a reduced risk of developing Parkinson's disease. [3] It is unresolved what caffeine's mechanism is on parkinsonian effects. It is believed it acts as an adenosine A2A receptor neutral antagonist or as an inverse agonist. Caffeine's A2A receptor inverse agonism may be the cause of the well-known physiological effects of this substance. [9]

Theophylline

Theophylline is a non-selective adenosine antagonist. It is also an anti-asthmatic agent and a demethylized 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. [3]

Istradefylline

Istradefylline Istradefylline.svg
Istradefylline

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. [10]

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. [4]

Mechanism of action

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. [5] 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. [7]

A2A receptors are G-protein coupled receptor (GPCR) that increases cyclic adenosine monophosphate (cAMP). [7] [1] These receptors are mainly expressed in the brain. [11] After almost a century of receptor research, the adenosine A2A receptor has been selected as a possible research target for various medical conditions. [1] Antagonists of the receptor have been researched, especially as an enhancer for the therapeutic effects of L-DOPA in Parkinson's treatment. [5]

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. [6] 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. [6] [2] [4]

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. [4]

Structure activity relationship (SAR)

Establishing the relationship between structure and efficacy for ligands of adenosine receptors has proven to be a challenge. In order to be able to characterize the function of adenosine A2 receptors, potent and selective A2-receptor antagonists were required. [12] Various chemical scaffolds of different SAR properties have been reported that show dramatic differences in activity once certain modifications are made. [5]

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

  1. Flat
  2. Aromatic or 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. [12] [5] [1] A2A agonists usually have a sugar moiety, which A2A antagonist 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. [12]

Core structure of xanthine based adenosine A2A antagonists Xanthines structure.png
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. Examples of core structures of monocyclic non-Xanthine based adenosine A2A antagonists.png
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. Examples of core structures of bicyclic non-Xanthine based adenosine A2A antagonists.png
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. Examples of core structures of tricyclic non-Xanthine based adenosine A2A antagonists.png
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. [1] 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. [1]

History

In 1929, adenosine was discovered as a naturally occurring nucleoside that can influence physiological functions. This discovery was made by Drury and Szent-Györgyi. [1] In the early 1930s the lability of adenosine was documented and the synthesis of more stable analogues began. Even before the first X-ray structures of the adenosine receptors were clarified, there were previously known various classes of adenosine antagonists. [7]

In 1965, the effects of caffeine on mammalian atrial muscle was documented by De Gubareffand Sleator. Then 5 years later, the effects of adenosine and adenine nucleotides on the cAMP in the guinea pig brain was described by Sattin and Rall. [1]

In 1980, methylxanthines caffeine and theophylline were observed in mice by Fredholm and others. They discovered that those substances stimulated and enhanced locomotor activity by blocking adenosine receptors. [1]

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">Theophylline</span> Drug used to treat respiratory diseases

Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors. It is used to treat chronic obstructive pulmonary disease (COPD) and asthma. Its pharmacology is similar to other methylxanthine drugs. Trace amounts of theophylline are naturally present in tea, coffee, chocolate, yerba maté, guarana, and kola nut.

<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">Adenosine receptor</span> Class of four receptor proteins to the molecule adenosine

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

<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.

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

An analeptic, in medicine, is a central nervous system stimulant. The term "analeptic" typically refers to respiratory stimulants. Analeptics are central nervous system (CNS) stimulants that include a wide variety of medications used to treat depression, attention deficit hyperactivity disorder (ADHD), and respiratory depression. Analeptics can also be used as convulsants, with low doses causing patients to experience heightened awareness, restlessness, and rapid breathing. The primary medical use of these drugs is as an anesthetic recovery tool or to treat emergency respiratory depression. Other drugs of this category are prethcamide, pentylenetetrazole, and nikethamide. Nikethamide is now withdrawn due to risk of convulsions. Analeptics have recently been used to better understand the treatment of a barbiturate overdose. Through the use of agents, researchers were able to treat obtundation and respiratory depression.

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.

<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">Istradefylline</span> Chemical compound

Istradefylline, sold under the brand name Nourianz, is a medication used as an add-on treatment to levodopa/carbidopa in adults with Parkinson's disease (PD) experiencing "off" episodes. Istradefylline reduces "off" periods resulting from long-term treatment with the antiparkinson drug levodopa. An "off" episode is a time when a patient's medications are not working well, causing an increase in PD symptoms, such as tremor and difficulty walking.

<span class="mw-page-title-main">ZM-241,385</span> Chemical compound

ZM-241,385 is a high affinity antagonist ligand selective for the adenosine A2A receptor.

<span class="mw-page-title-main">SCH-442,416</span> Chemical compound

SCH-442,416 is a highly selective adenosine A2a subtype receptor antagonist. It is widely used in its 11C radiolabelled form to map the distribution of A2a receptors in the brain, where they are mainly found in the striatum, nucleus accumbens, and olfactory tubercle. Given its distribution in the brain, A2a receptors have been investigated for the treatment of various neurological disorders, and SCH-442,416 has shown promise in treatment of depression, Parkinson's disease, and catalepsy.

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

Befiradol is an experimental drug being studied for the treatment of levodopa-induced dyskinesia. It is a potent and selective 5-HT1A receptor full agonist.

<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">8-Cyclopentyl-1,3-dimethylxanthine</span> Chemical compound

8-Cyclopentyl-1,3-dimethylxanthine (8-Cyclopentyltheophylline, 8-CPT, CPX) is a drug which acts as a potent and selective antagonist for the adenosine receptors, with some selectivity for the A1 receptor subtype, as well as a non-selective phosphodiesterase inhibitor. It has stimulant effects in animals with slightly higher potency than caffeine.

<span class="mw-page-title-main">8-Phenyltheophylline</span> Chemical compound

8-Phenyltheophylline (8-phenyl-1,3-dimethylxanthine, 8-PT) is a drug derived from the xanthine family which acts as a potent and selective antagonist for the adenosine receptors A1 and A2A, but unlike other xanthine derivatives has virtually no activity as a phosphodiesterase inhibitor. It has stimulant effects in animals with similar potency to caffeine. Coincidentally 8-phenyltheophylline has also been found to be a potent and selective inhibitor of the liver enzyme CYP1A2 which makes it likely to cause interactions with other drugs which are normally metabolised by CYP1A2.

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

Traxoprodil is a drug developed by Pfizer which acts as an NMDA antagonist, selective for the NR2B subunit. It has neuroprotective, analgesic, and anti-Parkinsonian effects in animal studies. Traxoprodil has been researched in humans as a potential treatment to lessen the damage to the brain after stroke, but results from clinical trials showed only modest benefit. The drug was found to cause EKG abnormalities and its clinical development was stopped. More recent animal studies have suggested traxoprodil may exhibit rapid-acting antidepressant effects similar to those of ketamine, although there is some evidence for similar psychoactive side effects and abuse potential at higher doses, which might limit clinical acceptance of traxoprodil for this application.

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

References

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  2. 1 2 Hurtado-Alvarado, G., Domínguez-Salazar, E., Velázquez-Moctezuma, J., & Gómez-González, B. (2016). A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction. PLOS ONE, Volume 11, Issue 11.
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  8. ↑ Sheng Tian, Xu Wang, Linlang Li, Xiaohu Zhang, Youyong Li, Feng Zhu, Tingjun Hou, and Xuechu Zhen
  9. ↑ Víctor Fernández-Dueñas, Maricel Gómez-Soler, Marc López-Cano, Jaume J. Taura, Catherine Ledent, Masahiko Watanabe, Kenneth A. Jacobson, Jean-Pierre Vilardaga and Francisco Ciruela. Uncovering Caffeine’s Adenosine A2A Receptor Inverse Agonism in Experimental Parkinsonism. ACS Chemical Biology. Volume 9. 2014. pp. 2496–2501.
  10. ↑ "FDA approves new add-on drug to treat off episodes in adults with Parkinson's disease". FDA approves new add-on drug to treat off episodes in adults with Parkinson’s disease. Archived from the original on 28 January 2018. Retrieved 7 October 2019.
  11. ↑ Sergi Ferre, Francisco Ciruela, Janusz Borycz, Marcello Solinas, Davide Quarta, Katerina Antoniu, Cesar Quiroz, Zuzana Justinova, Carme Lluis, Rafael Franco, and Steven R. Goldberg. Adenosine A1-A2A receptor heteromers: new targets for caffeine in the brain. Frontiers in Bioscience. Volume 13. Pages 2391-2399. 2008.
  12. 1 2 3 Kenneth A. Jacobson, Philip J. M. Van Galen, and Michael Williams Journal of Medicinal Chemistry 1992 35 (3), 407–422.
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