Paraxanthine

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Paraxanthine
Paraxanthine structure.svg
Paraxanthine 3D ball.png
Names
IUPAC name
1,7-Dimethyl-3H-purine-2,6-dione
Other names
Paraxanthine,
1,7-Dimethylxanthine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.009.339 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C7H8N4O2/c1-10-3-8-5-4(10)6(12)11(2)7(13)9-5/h3H,1-2H3,(H,9,13) Yes check.svgY
    Key: QUNWUDVFRNGTCO-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C7H8N4O2/c1-10-3-8-5-4(10)6(12)11(2)7(13)9-5/h3H,1-2H3,(H,9,13)
    Key: QUNWUDVFRNGTCO-UHFFFAOYAS
  • O=C2Nc1ncn(c1C(=O)N2C)C
Properties
C7H8N4O2
Molar mass 180.167 g·mol−1
Melting point 351 to 352 °C (664 to 666 °F; 624 to 625 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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.

Contents

Production and metabolism

Paraxanthine is not known to be produced by plants [1] but is observed in nature as a metabolite of caffeine in animals and some species of bacteria. [2]

Paraxanthine is the primary metabolite of caffeine in humans and other animals, such as mice. [3] Shortly after ingestion, roughly 84% of caffeine is metabolized into paraxanthine by hepatic cytochrome P450, which removes a methyl group from the N3 position of caffeine. [4] [5] [6] After formation, paraxanthine can be broken down to 7-methylxanthine by demethylation of the N1 position, [7] which is subsequently demethylated into xanthine or oxidized by CYP2A6 and CYP1A2 into 1,7-dimethyluric acid. [6] In another pathway, paraxanthine is broken down into 5-acetylamino-6-formylamino-3-methyluracil through N-acetyl-transferase 2, which is then broken down into 5-acetylamino-6-amino-3-methyluracil by non-enzymatic decomposition. [8] In yet another pathway, paraxanthine is metabolized CYPIA2 forming 1-methyl-xanthine, which can then be metabolized by xanthine oxidase to form 1-methyl-uric acid. [8]

Certain proposed synthetic pathways of caffeine make use of paraxanthine as a bypass intermediate. However, its absence in plant alkaloid assays implies that these are infrequently, if ever, directly produced by plants.[ citation needed ]

Pharmacology and physiological effects

Like caffeine, paraxanthine is a psychoactive central nervous system (CNS) stimulant. [2]

Pharmacodynamics

Studies indicate that, similar to caffeine, simultaneous antagonism of adenosine receptors [9] is responsible for paraxanthine's stimulatory effects. Paraxanthine adenosine receptor binding affinity (21 μM for A1, 32 μM for A2A, 4.5 μM for A2B, and >100 for μM for A3) is similar or slightly stronger than caffeine, but weaker than theophylline. [10]

Paraxanthine is a selective inhibitor of cGMP-preferring phosphodiesterase (PDE9) activity [11] and is hypothesized to increase glutamate and dopamine release by potentiating nitric oxide signaling. [12] Activation of a nitric oxide-cGMP pathway may be responsible for some of the behavioral effects of paraxanthine that differ from those associated with caffeine. [13]

Paraxanthine is a competitive nonselective phosphodiesterase inhibitor [14] which raises intracellular cAMP, activates PKA, inhibits TNF-alpha [15] [16] and leukotriene [17] synthesis, and reduces inflammation and innate immunity. [17]

Unlike caffeine, paraxanthine acts as an enzymatic effector of Na+/K+ ATPase. As a result, it is responsible for increased transport of potassium ions into skeletal muscle tissue. [18] Similarly, the compound also stimulates increases in calcium ion concentration in muscle. [19]

Pharmacokinetics

The pharmacokinetic parameter for paraxanthine are similar to those for caffeine, but differ significantly from those for theobromine and theophylline, the other major caffeine-derived methylxanthine metabolites in humans (Table 1).

Table 1. Comparative pharmacokinetics of caffeine, and caffeine-derived methylxanthines [20]
Plasma Half-Life

(t1/2; hr)

Volume of Distribution

(Vss,unbound; l/kg)

Plasma Clearance

(CL; ml/min/kg)

Caffeine 4.1 ± 1.31.06 ± 0.262.07 ± 0.96
Paraxanthine3.1 ± 0.81.18 ± 0.372.20 ± 0.91
Theobromine 7.2 ± 1.60.79 ± 0.151.20 ± 0.40
Theophylline 6.2 ± 1.40.77 ± 0.170.93 ± 0.22

Uses

Paraxanthine is a phosphodiesterase type 9 (PDE9) inhibitor and it is sold as a research molecule for this same purpose. [21]

Toxicity

Paraxanthine is believed to exhibit a lower toxicity than caffeine and the caffeine metabolite, theophylline. [22] [23] In a mouse model, intraperitoneal paraxanthine doses of 175 mg/kg/day did not result in animal death or overt signs of stress; [24] by comparison, the intraperitoneal LD50 for caffeine in mice is reported at 168 mg/kg. [25] In in vitro cell culture studies, paraxanthine is reported to be less harmful than caffeine and the least harmful of the caffeine-derived metabolites in terms of hepatocyte toxicity. [26]

As with other methylxanthines, paraxanthine is reported to be teratogenic when administered in high doses; [24] but it is a less potent teratogen as compared to caffeine and theophylline. A mouse study on the potentiating effects of methylxanthines coadministered with mitomycin C on teratogenicity reported the incidence of birth defects for caffeine, theophylline, and paraxanthine to be 94.2%, 80.0%, and 16.9%, respectively; additionally, average birth weight decreased significantly in mice exposed to caffeine or theophylline when coadministered with mitomycin C, but not for paraxanthine coadministered with mitomycin C. [27]

Paraxanthine was reported to be significantly less clastogenic compared to caffeine or theophylline in an in vitro study using human lymphocytes. [28]

Related Research Articles

<span class="mw-page-title-main">Caffeine</span> Central nervous system stimulant

Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class and is the most commonly consumed psychoactive substance globally. It is mainly used for its eugeroic, ergogenic, or nootropic properties. Caffeine acts by blocking binding of adenosine at a number of adenosine receptor types, inhibiting the centrally depressant effects of adenosine and enhancing the release of acetylcholine. Caffeine has a three-dimensional structure similar to that of adenosine, which allows it to bind and block its receptors. Caffeine also increases cyclic AMP levels through nonselective inhibition of phosphodiesterase, increases calcium release from intracellular stores, and antagonises GABA receptors, although these mechanisms typically occur at concentrations beyond usual human consumption.

<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">Theobromine</span> Bitter alkaloid of the cacao plant

Theobromine, also known as xantheose, is the principal alkaloid of Theobroma cacao. Theobromine is slightly water-soluble (330 mg/L) with a bitter taste. In industry, theobromine is used as an additive and precursor to some cosmetics. It is found in chocolate, as well as in a number of other foods, including tea, some American hollies and the kola nut. It is a white or colourless solid, but commercial samples can appear yellowish.

<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">Phosphodiesterase</span> Class of enzymes

A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases.

<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">IBMX</span> Chemical compound

IBMX (3-isobutyl-1-methylxanthine), like other methylxanthine 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.
<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">Doxofylline</span> Chemical compound

Doxofylline is a phosphodiesterase inhibiting bronchodilator used in the treatment of chronic respiratory diseases such as asthma and COPD. Like theophylline, it is a xanthine derivative.

<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">Theacrine</span> 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. Theacrine and caffeine are structurally similar.

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.

d9-Caffeine Deuterium-substituted isotopologue of caffeine

d9-Caffeine is a deuterium-substituted isotopologue of caffeine. It shares identical chemical and structural properties with conventional caffeine. except for the substitution of some or all of its hydrogen atoms with deuterium, a naturally occurring, non-toxic, stable, heavy isotope of hydrogen. Specifically, in d9-caffeine, the nine hydrogens contained in the three methyl groups of conventional caffeine have been replaced with deuterium.

References

  1. ↑ Stavric, B. (1988-01-01). "Methylxanthines: Toxicity to humans. 3. Theobromine, paraxanthine and the combined effects of methylxanthines". Food and Chemical Toxicology. 26 (8): 725–733. doi:10.1016/0278-6915(88)90073-7. ISSN   0278-6915. PMID   3058562.
  2. 1 2 Mazzafera P (May 2004). "Catabolism of caffeine in plants and microorganisms". Frontiers in Bioscience. 9 (1–3): 1348–59. doi: 10.2741/1339 . PMID   14977550.
  3. ↑ Fuhr U, Doehmer J, Battula N, Wölfel C, Flick I, Kudla C, Keita Y, Staib AH (October 1993). "Biotransformation of methylxanthines in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms. Allocation of metabolic pathways to isoforms and inhibitory effects of quinolones". Toxicology. 82 (1–3): 169–89. Bibcode:1993Toxgy..82..169F. doi:10.1016/0300-483x(93)90064-y. PMID   8236273.
  4. ↑ Guerreiro S, Toulorge D, Hirsch E, Marien M, Sokoloff P, Michel PP (October 2008). "Paraxanthine, the primary metabolite of caffeine, provides protection against dopaminergic cell death via stimulation of ryanodine receptor channels". Molecular Pharmacology. 74 (4): 980–9. doi:10.1124/mol.108.048207. PMID   18621927. S2CID   14842240.
  5. ↑ Graham TE, Rush JW, van Soeren MH (June 1994). "Caffeine and exercise: metabolism and performance". Canadian Journal of Applied Physiology. 19 (2): 111–38. doi:10.1139/h94-010. PMID   8081318.
  6. 1 2 Mazzafera P (May 2004). "Catabolism of caffeine in plants and microorganisms". Frontiers in Bioscience. 9 (1–3): 1348–59. doi: 10.2741/1339 . PMID   14977550.
  7. ↑ Summers RM, Mohanty SK, Gopishetty S, Subramanian M (May 2015). "Genetic characterization of caffeine degradation by bacteria and its potential applications". Microbial Biotechnology. 8 (3): 369–78. doi:10.1111/1751-7915.12262. PMC   4408171 . PMID   25678373.
  8. 1 2 Caffeine : chemistry, analysis, function and effects. Preedy, Victor R.,, Royal Society of Chemistry (Great Britain). Cambridge, U.K. 2012. ISBN   9781849734752. OCLC   810337257.{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: others (link)
  9. ↑ Daly JW, Jacobson KA, Ukena D (1987). "Adenosine receptors: development of selective agonists and antagonists". Progress in Clinical and Biological Research. 230 (1): 41–63. PMID   3588607.
  10. ↑ Müller, Christa E.; Jacobson, Kenneth A. (2011), Fredholm, Bertil B. (ed.), "Xanthines as Adenosine Receptor Antagonists", Methylxanthines, Handbook of Experimental Pharmacology, vol. 200, no. 200, Springer, pp. 151–199, doi:10.1007/978-3-642-13443-2_6, ISBN   978-3-642-13443-2, PMC   3882893 , PMID   20859796
  11. ↑ Orrú, Marco; Guitart, Xavier; Karcz-Kubicha, Marzena; Solinas, Marcello; Justinova, Zuzana; Barodia, Sandeep Kumar; Zanoveli, Janaina; Cortes, Antoni; Lluis, Carme; Casado, Vicent; Moeller, F. Gerard (April 2013). "Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans". Neuropharmacology. 67C: 476–484. doi:10.1016/j.neuropharm.2012.11.029. ISSN   0028-3908. PMC   3562388 . PMID   23261866.
  12. ↑ Ferré, Sergi; Orrú, Marco; Guitart, Xavier (2013). "Paraxanthine: Connecting Caffeine to Nitric Oxide Neurotransmission". Journal of Caffeine Research. 3 (2): 72–78. doi:10.1089/jcr.2013.0006. ISSN   2156-5783. PMC   3680978 . PMID   24761277.
  13. ↑ Orrú, Marco (2013). "Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans". Neuropharmacology. 67C: 476–484. doi:10.1016/j.neuropharm.2012.11.029. PMC   3562388 . PMID   23261866.
  14. ↑ Essayan DM (November 2001). "Cyclic nucleotide phosphodiesterases". The Journal of Allergy and Clinical Immunology. 108 (5): 671–80. doi: 10.1067/mai.2001.119555 . PMID   11692087.
  15. ↑ Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R (June 2008). "Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition". Clinics. 63 (3): 321–8. doi:10.1590/S1807-59322008000300006. PMC   2664230 . PMID   18568240.
  16. ↑ Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". American Journal of Respiratory and Critical Care Medicine. 159 (2): 508–11. doi:10.1164/ajrccm.159.2.9804085. PMID   9927365.
  17. 1 2 Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (January 2005). "Leukotrienes: underappreciated mediators of innate immune responses". Journal of Immunology. 174 (2): 589–94. doi: 10.4049/jimmunol.174.2.589 . PMID   15634873.
  18. ↑ Hawke TJ, Willmets RG, Lindinger MI (November 1999). "K+ transport in resting rat hind-limb skeletal muscle in response to paraxanthine, a caffeine metabolite". Canadian Journal of Physiology and Pharmacology. 77 (11): 835–43. doi:10.1139/y99-095. PMID   10593655.
  19. ↑ Hawke TJ, Allen DG, Lindinger MI (December 2000). "Paraxanthine, a caffeine metabolite, dose dependently increases [Ca(2+)](i) in skeletal muscle". Journal of Applied Physiology. 89 (6): 2312–7. doi: 10.1152/jappl.2000.89.6.2312 . PMID   11090584. S2CID   11369121.
  20. ↑ Lelo, A.; Birkett, D. J.; Robson, R. A.; Miners, J. O. (August 1986). "Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man". British Journal of Clinical Pharmacology. 22 (2): 177–182. doi:10.1111/j.1365-2125.1986.tb05246.x. ISSN   0306-5251. PMC   1401099 . PMID   3756065.
  21. ↑ "Paraxanthine" (PDF).
  22. ↑ Neal L. Benowitz; Peyton Jacob; Haim Mayan; Charles Denaro (1995). "Sympathomimetic effects of paraxanthine and caffeine in humans". Clinical Pharmacology & Therapeutics. 58 (6): 684–691. doi:10.1016/0009-9236(95)90025-X. PMID   8529334. S2CID   22747642.
  23. ↑ Institute of Medicine (US) Committee on Military Nutrition Research (2001). Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations. Washington (DC): National Academies Press (US). ISBN   978-0-309-08258-7. PMID   25057583.
  24. 1 2 York, R. G.; Randall, J. L.; Scott, W. J. (1986). "Teratogenicity of paraxanthine (1,7-dimethylxanthine) in C57BL/6J mice". Teratology. 34 (3): 279–282. doi:10.1002/tera.1420340307. ISSN   0040-3709. PMID   3798364.
  25. ↑ Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. 1987.
  26. ↑ Gressner, Olav A.; Lahme, Birgit; Siluschek, Monika; Gressner, Axel M. (2009). "Identification of paraxanthine as the most potent caffeine-derived inhibitor of connective tissue growth factor expression in liver parenchymal cells". Liver International. 29 (6): 886–897. doi:10.1111/j.1478-3231.2009.01987.x. ISSN   1478-3231. PMID   19291178. S2CID   32926935.
  27. ↑ Nakatsuka, Toshio; Hanada, Satoshi; Fujii, Takaaki (1983). "Potentiating effects of methylxanthines on teratogenicity of mitomycin C in mice". Teratology. 28 (2): 243–247. doi:10.1002/tera.1420280214. ISSN   1096-9926. PMID   6417813.
  28. ↑ Weinstein, David; Mauer, Irving; Katz, Marion L.; Kazmer, Sonja (1975). "The effect of methylxanthines on chromosomes of human lymphocytes in culture". Mutation Research/Environmental Mutagenesis and Related Subjects. 31 (1): 57–61. doi:10.1016/0165-1161(75)90064-3. ISSN   0165-1161. PMID   1128545.
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