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{{chembox| Verifiedfields = changed| Watchedfields = changed| verifiedrevid = 464197387| Name = Paraxanthine| ImageFile = Paraxanthine structure.svg| ImageSize = 150| ImageName = Skeletal formula of paraxanthine| ImageFile1 = Paraxanthine 3D ball.png| ImageSize1 = 180| ImageAlt1 = Ball-and-stick model of the paraxanthine model| IUPACName = 1,7-Dimethyl-3H-purine-2,6-dione| OtherNames = Paraxanthine, 1,7-Dimethylxanthine| Section1 = {{Chembox Identifiers|Caffeine|4.1 ± 1.3|1.06 ± 0.26|2.07 ± 0.96|Paraxanthine|3.1 ± 0.8|1.18 ± 0.37|2.20 ± 0.91|Theobromine|7.2 ± 1.6|0.79 ± 0.15|1.20 ± 0.40|Theophylline|6.2 ± 1.4|0.77 ± 0.17|0.93 ± 0.22

Plasma Half-Life(t1/2; hr)!Volume of Distribution(Vss,unbound; l/kg)!Plasma Clearance(CL; ml/min/kg)

correct|FDA}}| UNII = Q3565Y41V7	correct|EBI}}| ChEBI = 25858| SMILES = O=C2Nc1ncn(c1C(=O)N2C)C	correct|chemspider}}| ChemSpiderID = 4525| PubChem = 4687| InChI = 1/C7H8N4O2/c1-10-3-8-5-4(10)6(12)11(2)7(13)9-5/h3H,1-2H3,(H,9,13)| InChIKey = QUNWUDVFRNGTCO-UHFFFAOYAS	correct|EBI}}| ChEMBL = 1158	correct|chemspider}}| StdInChI = 1S/C7H8N4O2/c1-10-3-8-5-4(10)6(12)11(2)7(13)9-5/h3H,1-2H3,(H,9,13)	correct|chemspider}}| StdInChIKey = QUNWUDVFRNGTCO-UHFFFAOYSA-N	changed|??}}| CASNo = 611-59-6}}| Section2 = {{Chembox Properties	H=8	O=2| MeltingPtC = 351 to 352}}}}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. Production and metabolism Paraxanthine is not known to be produced by plantsJOURNAL, Stavric, B., 1988-01-01, Methylxanthines: Toxicity to humans. 3. Theobromine, paraxanthine and the combined effects of methylxanthines, Food and Chemical Toxicology, en, 26, 8, 725–733, 10.1016/0278-6915(88)90073-7, 3058562, 0278-6915, but is observed in nature as a metabolite of caffeine in animals and some species of bacteria.JOURNAL, Mazzafera P, Catabolism of caffeine in plants and microorganisms, Frontiers in Bioscience, 9, 1–3, 1348–59, May 2004, 14977550, 10.2741/1339, free, Paraxanthine is the primary metabolite of caffeine in humans and other animals, such as mice.JOURNAL, Fuhr U, Doehmer J, Battula N, Wölfel C, Flick I, Kudla C, Keita Y, Staib AH, 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, October 1993, 8236273, 10.1016/0300-483x(93)90064-y, 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.JOURNAL, Guerreiro S, Toulorge D, Hirsch E, Marien M, Sokoloff P, Michel PP, Paraxanthine, the primary metabolite of caffeine, provides protection against dopaminergic cell death via stimulation of ryanodine receptor channels, Molecular Pharmacology, 74, 4, 980–9, October 2008, 18621927, 10.1124/mol.108.048207, 14842240, JOURNAL, Graham TE, Rush JW, van Soeren MH, Caffeine and exercise: metabolism and performance, Canadian Journal of Applied Physiology, 19, 2, 111–38, June 1994, 8081318, 10.1139/h94-010, JOURNAL, Mazzafera P, Catabolism of caffeine in plants and microorganisms, Frontiers in Bioscience, 9, 1–3, 1348–59, May 2004, 14977550, 10.2741/1339, free, After formation, paraxanthine can be broken down to 7-methylxanthine by demethylation of the N1 position,JOURNAL, Summers RM, Mohanty SK, Gopishetty S, Subramanian M, Genetic characterization of caffeine degradation by bacteria and its potential applications, Microbial Biotechnology, 8, 3, 369–78, May 2015, 25678373, 4408171, 10.1111/1751-7915.12262, which is subsequently demethylated into xanthine or oxidized by CYP2A6 and CYP1A2 into 1,7-dimethyluric acid. 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.BOOK, Caffeine : chemistry, analysis, function and effects, Preedy, Victor R.,, Royal Society of Chemistry (Great Britain), 9781849734752, Cambridge, U.K., 810337257, 2012, 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.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|date=September 2008}} Pharmacology and physiological effects {{more medical citations|section|date=November 2021}}Like caffeine, paraxanthine is a psychoactive central nervous system (CNS) stimulant. Pharmacodynamics Studies indicate that, similar to caffeine, simultaneous antagonism of adenosine receptorsJOURNAL, 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, 3588607, 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.{{Citation|last1=Müller|first1=Christa E.|title=Xanthines as Adenosine Receptor Antagonists|date=2011|work=Methylxanthines|pages=151–199|editor-last=Fredholm|editor-first=Bertil B.|series=Handbook of Experimental Pharmacology|publisher=Springer|language=en|doi=10.1007/978-3-642-13443-2_6|isbn=978-3-642-13443-2|pmc=3882893|pmid=20859796|last2=Jacobson|first2=Kenneth A.|volume=200 |issue=200}}Paraxanthine is a selective inhibitor of cGMP-preferring phosphodiesterase (PDE9) activityJOURNAL, 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, 10.1016/j.neuropharm.2012.11.029, 0028-3908, 3562388, 23261866, and is hypothesized to increase glutamate and dopamine release by potentiating nitric oxide signaling.JOURNAL, Ferré, Sergi, Orrú, Marco, Guitart, Xavier, 2013, Paraxanthine: Connecting Caffeine to Nitric Oxide Neurotransmission, Journal of Caffeine Research, 3, 2, 72–78, 10.1089/jcr.2013.0006, 2156-5783, 3680978, 24761277, 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.JOURNAL, Orrú, Marco, 2013, Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans, Neuropharmacology, 67C, 476–484, 3562388, 23261866, 10.1016/j.neuropharm.2012.11.029, Paraxanthine is a competitive nonselective phosphodiesterase inhibitorJOURNAL, Essayan DM, Cyclic nucleotide phosphodiesterases, The Journal of Allergy and Clinical Immunology, 108, 5, 671–80, November 2001, 11692087, 10.1067/mai.2001.119555, free, which raises intracellular cAMP, activates PKA, inhibits TNF-alphaJOURNAL, Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R, Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition, Clinics, 63, 3, 321–8, June 2008, 18568240, 2664230, 10.1590/S1807-59322008000300006, JOURNAL, Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U, Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages, American Journal of Respiratory and Critical Care Medicine, 159, 2, 508–11, February 1999, 9927365, 10.1164/ajrccm.159.2.9804085, and leukotrieneJOURNAL, Peters-Golden M, Canetti C, Mancuso P, Coffey MJ, Leukotrienes: underappreciated mediators of innate immune responses, Journal of Immunology, 174, 2, 589–94, January 2005, 15634873, 10.4049/jimmunol.174.2.589,www.jimmunol.org/cgi/content/full/174/2/589, free, synthesis, and reduces inflammation and innate immunity.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.JOURNAL, Hawke TJ, Willmets RG, Lindinger MI, 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, November 1999, 10593655, 10.1139/y99-095, Similarly, the compound also stimulates increases in calcium ion concentration in muscle.JOURNAL, Hawke TJ, Allen DG, Lindinger MI, Paraxanthine, a caffeine metabolite, dose dependently increases [Ca(2+)](i) in skeletal muscle, Journal of Applied Physiology, 89, 6, 2312–7, December 2000, 11090584, 10.1152/jappl.2000.89.6.2312, 11369121, free, 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).{| class=“wikitable”

Uses

Paraxanthine is a phosphodiesterase type 9 (PDE9) inhibitor and it is sold as a research molecule for this same purpose.WEB,www.caymanchem.com/pdfs/21068.pdf, Paraxanthine,

Toxicity

Paraxanthine is believed to exhibit a lower toxicity than caffeine and the caffeine metabolite, theophylline.JOURNAL, Clinical Pharmacology & Therapeutics, 1995, 6, 684–691, Sympathomimetic effects of paraxanthine and caffeine in humans, Neal L. Benowitz, Peyton Jacob, Haim Mayan, Charles Denaro,www.nature.com/clpt/journal/v58/n6/abs/clpt1995184a.html, 10.1016/0009-9236(95)90025-X, 8529334, 58, 22747642, BOOK, Institute of Medicine (US) Committee on Military Nutrition Research,www.ncbi.nlm.nih.gov/books/NBK223802/, Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations, 2001, National Academies Press (US), 978-0-309-08258-7, Washington (DC), 25057583, In a mouse model, intraperitoneal paraxanthine doses of 175 mg/kg/day did not result in animal death or overt signs of stress;JOURNAL, 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, 10.1002/tera.1420340307, 0040-3709, 3798364, by comparison, the intraperitoneal LD50 for caffeine in mice is reported at 168 mg/kg.BOOK,books.google.com/books?id=fDVaIb9H7DAC&q=caffeine+mouse+LD50+intraperitoneal+168+mg%2Fkg&pg=PA1373, Registry of Toxic Effects of Chemical Substances, 1987, National Institute for Occupational Safety and Health, en, 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.JOURNAL, 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, 10.1111/j.1478-3231.2009.01987.x, 1478-3231, 19291178, 32926935, As with other methylxanthines, paraxanthine is reported to be teratogenic when administered in high doses; 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.JOURNAL, Nakatsuka, Toshio, Hanada, Satoshi, Fujii, Takaaki, 1983, Potentiating effects of methylxanthines on teratogenicity of mitomycin C in mice, Teratology, en, 28, 2, 243–247, 10.1002/tera.1420280214, 6417813, 1096-9926, Paraxanthine was reported to be significantly less clastogenic compared to caffeine or theophylline in an in vitro study using human lymphocytes.JOURNAL, 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, en, 31, 1, 57–61, 10.1016/0165-1161(75)90064-3, 1128545, 0165-1161,

References

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External links

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