Xanthine

Last updated
Xanthine [1]
Xanthin - Xanthine.svg
Xanthine-3D-balls.png
Names
IUPAC name
3,7-Dihydropurine-2,6-dione
Other names
1H-Purine-2,6-dione
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.653
KEGG
PubChem CID
UNII
Properties
C5H4N4O2
Molar mass 152.11 g/mol
AppearanceWhite solid
Melting point decomposes
1 g/ 14.5 L @ 16 °C
1 g/1.4 L @ 100 °C
Hazards
NFPA 704 (fire diamond)
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilHealth code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no codeXanthine
1
2
0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Xanthine ( /ˈzænθn/ or /ˈzænθn/ ; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids and in other organisms. [2] Several stimulants are derived from xanthine, including caffeine and theobromine. [3]

Purine chemical compound

Purine is a heterocyclic aromatic organic compound that consists of a pyrimidine ring fused to an imidazole ring. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines and their tautomers. They are the most widely occurring nitrogen-containing heterocycles in nature.

Stimulant type of psychoactive drug

Stimulants is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and invigorating, or drugs that have sympathomimetic effects. Stimulants are widely used throughout the world as prescription medicines as well as without a prescription as performance-enhancing or recreational drugs. The most frequently prescribed stimulants as of 2013 were lisdexamfetamine, methylphenidate, and amphetamine. It is estimated that the percentage of the population that has abused amphetamine-type stimulants and cocaine combined is between 0.8% and 2.1%.

Caffeine A central nervous system stimulant

Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is the world's most widely consumed psychoactive drug. Unlike many other psychoactive substances, it is legal and unregulated in nearly all parts of the world. There are several known mechanisms of action to explain the effects of caffeine. The most prominent is that it reversibly blocks the action of adenosine on its receptor and consequently prevents the onset of drowsiness induced by adenosine. Caffeine also stimulates certain portions of the autonomic nervous system.

Contents

Xanthine is a product on the pathway of purine degradation. [2]

Guanine Chemical compound of DNA and RNA

Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine. In DNA, guanine is paired with cytosine. The guanine nucleoside is called guanosine.

Guanine deaminase mammalian protein found in Homo sapiens

Guanine deaminase also known as cypin, guanase, guanine aminase, GAH, and guanine aminohydrolase is an aminohydrolase enzyme which converts guanine to xanthine. Cypin is a major cytosolic protein that interacts with PSD-95. It promotes localized microtubule assembly in neuronal dendrites.

Hypoxanthine chemical compound

Hypoxanthine is a naturally occurring purine derivative. It is occasionally found as a constituent of nucleic acids, where it is present in the anticodon of tRNA in the form of its nucleoside inosine. It has a tautomer known as 6-hydroxypurine. Hypoxanthine is a necessary additive in certain cell, bacteria, and parasite cultures as a substrate and nitrogen source. For example, it is commonly a required reagent in malaria parasite cultures, since Plasmodium falciparum requires a source of hypoxanthine for nucleic acid synthesis and energy metabolism.

Xanthine is subsequently converted to uric acid by the action of the xanthine oxidase enzyme. [2]

Uric acid the end product of nucleic acid degradation

Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of purine nucleotides, and it is a normal component of urine. High blood concentrations of uric acid can lead to gout and are associated with other medical conditions, including diabetes and the formation of ammonium acid urate kidney stones.

Xanthine oxidase class of enzymes

Xanthine oxidase is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid. These enzymes play an important role in the catabolism of purines in some species, including humans.

Use and manufacturing

Xanthine is used as a drug precursor for human and animal medications, and is manufactured as a pesticide ingredient. [2]

Drug Substance having an effect on the body

A drug is any substance that causes a change in an organism's physiology or psychology when consumed.

In chemistry, a precursor is a compound that participates in a chemical reaction that produces another compound.

Pesticide substance used to destroy pests

Pesticides are substances that are meant to control pests, including weeds. The term pesticide includes all of the following: herbicide, insecticides nematicide, molluscicide, piscicide, avicide, rodenticide, bactericide, insect repellent, animal repellent, antimicrobial, and fungicide. The most common of these are herbicides which account for approximately 80% of all pesticide use. Most pesticides are intended to serve as plant protection products, which in general, protect plants from weeds, fungi, or insects.

Clinical significance

Derivatives of xanthine (known collectively as xanthines) are a group of alkaloids commonly used for their effects as mild stimulants and as bronchodilators, notably in the treatment of asthma or influenza symptoms. [2] In contrast to other, more potent stimulants like sympathomimetic amines, xanthines mainly act to oppose the actions of adenosine, and increase alertness in the central nervous system. [2]

Alkaloid class of naturally occurring chemical compounds

Alkaloids are a class of naturally occurring organic compounds that mostly contain basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar structure may also be termed alkaloids. In addition to carbon, hydrogen and nitrogen, alkaloids may also contain oxygen, sulfur and, more rarely, other elements such as chlorine, bromine, and phosphorus.

A bronchodilator is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs. Bronchodilators may be endogenous, or they may be medications administered for the treatment of breathing difficulties. They are most useful in obstructive lung diseases, of which asthma and chronic obstructive pulmonary disease are the most common conditions. Although this remains somewhat controversial, they might be useful in bronchiolitis and bronchiectasis. They are often prescribed but of unproven significance in restrictive lung diseases.

Asthma long-term disease involving poor airflow in the lungs

Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, coughing, chest tightness, and shortness of breath. These may occur a few times a day or a few times per week. Depending on the person, asthma symptoms may become worse at night or with exercise.

Toxicity

Due to widespread effects, the therapeutic range of xanthine is narrow, making it merely a second-line asthma treatment. The therapeutic level is 10-20 micrograms/mL blood; signs of toxicity include tremor, nausea, nervousness, and tachycardia/arrhythmia.

Methylated xanthines (methylxanthines), which include caffeine, aminophylline, IBMX, paraxanthine, pentoxifylline, theobromine, and theophylline, affect not only the airways but stimulate heart rate, force of contraction, and cardiac arrhythmias at high concentrations. [2] In high doses, they can lead to convulsions that are resistant to anticonvulsants. [2] Methylxanthines induce acid and pepsin secretions in the gastrointestinal tract. [2] Methylxanthines are metabolized by cytochrome P450 in the liver. [2]

If swallowed, inhaled, or exposed to the eyes in high amounts, xanthines can be harmful, and may cause an allergic reaction if applied topically. [2]

Pharmacology

In in vitro pharmacological studies, xanthines act as both:

  1. competitive nonselective phosphodiesterase inhibitors which raise intracellular cAMP, activate PKA, inhibit TNF-α [2] [4] and leukotriene [5] synthesis, and reduce inflammation and innate immunity [5] and
  2. nonselective adenosine receptor antagonists [6] which inhibit sleepiness-inducing adenosine. [2]

But different analogues show varying potency at the numerous subtypes, and a wide range of synthetic xanthines (some nonmethylated) have been developed searching for compounds with greater selectivity for phosphodiesterase enzyme or adenosine receptor subtypes. [2] [7] [8] [9] [10] [11]

Xanthine: R1 = R2 = R3 = H
Caffeine: R1 = R2 = R3 = CH3
Theobromine: R1 = H, R2 = R3 = CH3
Theophylline: R1 = R2 = CH3, R3 = H Methylxanthine.png
Xanthine: R1 = R2 = R3 = H
Caffeine: R1 = R2 = R3 = CH3
Theobromine: R1 = H, R2 = R3 = CH3
Theophylline: R1 = R2 = CH3, R3 = H
Examples of xanthine derivatives
NameR1R2R3R8 IUPAC nomenclature Found in
XanthineHHHH3,7-Dihydro-purine-2,6-dionePlants, animals
Caffeine CH3 CH3 CH3 H1,3,7-Trimethyl-1H-purine-2,6(3H,7H)-dione Coffee, guarana, yerba mate, tea, kola, guayusa, holly
Theobromine H CH3 CH3 H3,7-Dihydro-3,7-dimethyl-1H-purine-2,6-dione Cacao (chocolate), yerba mate, kola, guayusa, holly
Theophylline CH3 CH3 HH1,3-Dimethyl-7H-purine-2,6-dione Tea, cacao (chocolate), yerba mate, kola
Paraxanthine CH3 H CH3 H1,7-Dimethyl-7H-purine-2,6-dioneAnimals that have consumed caffeine
8-Chlorotheophylline CH3 CH3 HCl8-Chloro-1,3-dimethyl-7H-purine-2,6-dioneSynthetic pharmaceutical ingredient
Diprophylline CH3 CH3 C3H7O2H7-(2,3-Dihydroxypropyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dioneSynthetic pharmaceutical ingredient
IBMX CH3 C4H9 HH1-Methyl-3-(2-methylpropyl)-7H-purine-2,6-dione
Uric acid HHHO7,9-Dihydro-1H-purine-2,6,8(3H)-trioneByproduct of purine nucleotides metabolism and a normal component of urine

Pathology

People with the rare genetic disorders, specifically xanthinuria and Lesch-Nyhan syndrome, lack sufficient xanthine oxidase and cannot convert xanthine to uric acid. [2]

Speculation on origin

Studies reported in 2008, based on 12C/13C isotopic ratios of organic compounds found in the Murchison meteorite, suggested that xanthine and related chemicals, including the RNA component uracil, were formed extraterrestrially. [12] [13] In August 2011, a report, based on NASA studies with meteorites found on Earth, was published suggesting xanthine and related organic molecules, including the DNA and RNA components adenine and guanine, were found in outer space. [14] [15] [16]

See also

Related Research Articles

Phosphodiesterase inhibitor compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases

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.

Theobromine chemical compound

Theobromine, formerly known as xantheose, is a bitter alkaloid of the cacao plant, with the chemical formula C7H8N4O2. It is found in chocolate, as well as in a number of other foods, including the leaves of the tea plant, and the kola nut. It is classified as a xanthine alkaloid, others of which include theophylline and caffeine. Caffeine differs from the compounds in that it has an extra methyl group (see under Pharmacology section).

Theophylline chemical compound

Theophylline, also known as 1,3-dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the xanthine family, it bears structural and pharmacological similarity to theobromine and caffeine, and is readily found in nature, being present in tea and cocoa. A small amount of theophylline is one of the products of caffeine metabolic processing in the liver.

Adenosine chemical compound

Adenosine is both a chemical found in many living systems and a medication. As a medication it is used to treat certain forms of supraventricular tachycardia that do not improve with vagal maneuvers. Common side effects include chest pain, feeling faint, shortness of breath and tingling of the senses. Serious side effects include increased dysrhythmia and reduced blood pressure. It appears to be safe in pregnancy.

Aminophylline 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.

Paraxanthine chemical compound

Paraxanthine, or 1,7-dimethylxanthine, is a dimethyl derivative of xanthine, structurally related to caffeine. Like caffeine, paraxanthine is a psychoactive central nervous system (CNS) stimulant. It possesses a potency roughly equal to that of caffeine and is likely involved in the mediation of the effects of caffeine itself.

Analeptic Drug class

An analeptic, in medicine, is a central nervous system stimulant. The term analeptic typically refers to respiratory analeptics. Analeptics are central nervous system 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.

8-Chlorotheophylline chemical compound

8-Chlorotheophylline, also known as 1,3-dimethyl-8-chloroxanthine, is a stimulant drug of the xanthine chemical class, with physiological effects similar to caffeine. Its main use is in combination (salt) with diphenhydramine in the antiemetic dimenhydrinate. Diphenhydramine reduces nausea but causes drowsiness, and the stimulant properties of 8-Chlorotheophylline help ward off that side-effect.

Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.

IBMX chemical compound

IBMX (3-isobutyl-1-methylxanthine), like other methylated xanthine derivatives, is both a:

  1. competitive non-selective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNFα and leukotriene synthesis, and reduces inflammation and innate immunity, and
  2. nonselective adenosine receptor antagonist.
Dipropylcyclopentylxanthine 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.

SCH-58261 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 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 and neuroprotective effects in a variety of animal models, and has been investigated as a possible treatment for Parkinson's disease.

Cartazolate chemical compound

Cartazolate (SQ-65,396) is a drug of the pyrazolopyridine class. It acts as a GABAA receptor positive allosteric modulator at the barbiturate binding site of the complex and has anxiolytic effects in animals. It is also known to act as an adenosine antagonist at the A1 and A2 subtypes and as a phosphodiesterase inhibitor. Cartazolate was tested in human clinical trials and was found to be efficacious for anxiety but was never marketed. It was developed by a team at E.R. Squibb and Sons in the 1970s.

CGS-15943 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.

8-Cyclopentyl-1,3-dimethylxanthine 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.

8-Phenyltheophylline 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.

Theacrine chemical compound

Theacrine, also known as 1,3,7,9-tetramethyluric acid, is a purine alkaloid found in Cupuaçu and in a Chinese tea known as kucha. It shows anti-inflammatory and analgesic effects and appears to affect adenosine signalling in a manner similar to caffeine. In kucha leaves, theacrine is synthesized from caffeine in what is thought to be a three-step pathway.

An adenosine receptor antagonist is a drug which acts as an antagonist of one or more of the adenosine receptors. Examples include caffeine, theophylline, and theobromine.

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.

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