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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.

Contents

1 Production and metabolism 2 Physiological effects 3 Toxicity 4 References 5 External links

Production and metabolism[edit] Paraxanthine
Paraxanthine
is not produced by plants[citation needed] and is only observed in nature as a metabolite of caffeine in animals. After intake, roughly 84% of caffeine is demethylated at the 3-position to yield paraxanthine, making it the chief metabolite of caffeine in the body.[1] 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] Physiological effects[edit] Paraxanthine
Paraxanthine
has a number of physiological effects on animals:

Paraxanthine
Paraxanthine
is a competitive nonselective phosphodiesterase inhibitor[2] which raises intracellular cAMP, activates PKA, inhibits TNF-alpha[3][4] and leukotriene[5] synthesis, and reduces inflammation and innate immunity.[5] Paraxanthine
Paraxanthine
is a nonselective adenosine receptor antagonist[6] which raises plasma epinephrine and diastolic blood pressure. Paraxanthine
Paraxanthine
may be responsible for the lipolytic properties of caffeine, and its presence in the blood causes an increase in serum free fatty acid concentration.[7] Paraxanthine, unlike caffeine, 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.[8] Similarly, the compound also stimulates increases in calcium ion concentration in muscle.[9]

Toxicity[edit] Paraxanthine
Paraxanthine
is believed to exhibit a lower toxicity than caffeine.[10] While blood levels commensurate with average intake appear to be fairly innocuous, high blood concentrations of paraxanthine have been linked to miscarriage in pregnant mothers.[11] References[edit]

^ 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". Mol. Pharmacol. 74 (4): 980–9. doi:10.1124/mol.108.048207. PMID 18621927.  ^ Essayan DM. (2001). "Cyclic nucleotide phosphodiesterases". J Allergy Clin Immunol. 108 (5): 671–80. doi:10.1067/mai.2001.119555. PMID 11692087.  ^ Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R (2008). "Insights into the Regulation of TNF-α Production in Human Mononuclear Cells: The Effects of Non-Specific Phosphodiesterase Inhibition". Clinics (Sao Paulo). 63 (3): 321–8. doi:10.1590/S1807-59322008000300006. PMC 2664230 . PMID 18568240.  ^ Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). " Pentoxifylline
Pentoxifylline
inhibits TNF-alpha production from human alveolar macrophages". Am. J. Respir. Crit. Care Med. 159 (2): 508–11. doi:10.1164/ajrccm.159.2.9804085. PMID 9927365.  ^ a b Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (2005). "Leukotrienes: underappreciated mediators of innate immune responses". J. Immunol. 174 (2): 589–94. doi:10.4049/jimmunol.174.2.589. PMID 15634873.  ^ Daly JW, Jacobson KA, Ukena D (1987). " Adenosine
Adenosine
receptors: development of selective agonists and antagonists". Prog Clin Biol Res. 230 (1): 41–63. PMID 3588607.  ^ Hetzler RK, Knowlton RG, Somani SM, Brown DD, Perkins RM (January 1990). "Effect of paraxanthine on FFA mobilization after intravenous caffeine administration in humans (Bethesda MD 1985)". Journal of Applied Physiology. 68 (1): 44–47. doi:10.1152/jappl.1990.68.1.44. PMID 2312486.  ^ 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): 835–843. doi:10.1139/y99-095. PMID 10593655.  ^ 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): 2312–2317. doi:10.1152/jappl.2000.89.6.2312. PMID 11090584.  ^ 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.  ^ Mark A. Klebanoff; Richard J. Levine; Rebecca DerSimonian.; John D. Clemens; Diana G. Wilkins (1999). "Maternal Serum Paraxanthine, a Caffeine
Caffeine
Metabolite, and the Risk of Spontaneous Abortion". New England Journal of Medicine. 341 (22): 1639–1644. doi:10.1056/NEJM199911253412202. PMID 10572151. 

External links[edit]

Media related to Paraxanthine
Paraxanthine
at Wikimedia Commons

v t e

Stimulants

Adamantanes

Adapromine Amantadine Bromantane Memantine Rimantadine

Adenosine
Adenosine
antagonists

8-Chlorotheophylline 8-Cyclopentyltheophylline 8-Phenyltheophylline Aminophylline Caffeine CGS-15943 Dimethazan Paraxanthine SCH-58261 Theobromine Theophylline

Alkylamines

Cyclopentamine Cypenamine Cyprodenate Heptaminol Isometheptene Levopropylhexedrine Methylhexaneamine Octodrine Propylhexedrine Tuaminoheptane

Ampakines

CX-516 CX-546 CX-614 CX-691 CX-717 IDRA-21 LY-404,187 LY-503,430 Nooglutyl Org 26576 PEPA S-18986 Sunifiram Unifiram

Arylcyclohexylamines

Benocyclidine Dieticyclidine Esketamine Eticyclidine Gacyclidine Ketamine Phencyclamine Phencyclidine Rolicyclidine Tenocyclidine Tiletamine

Benzazepines

6-Br-APB SKF-77434 SKF-81297 SKF-82958

Cholinergics

A-84,543 A-366,833 ABT-202 ABT-418 AR-R17779 Altinicline Anabasine Arecoline Bradanicline Cotinine Cytisine Dianicline Epibatidine Epiboxidine GTS-21 Ispronicline Nicotine PHA-543,613 PNU-120,596 PNU-282,987 Pozanicline Rivanicline Sazetidine A SIB-1553A SSR-180,711 TC-1698 TC-1827 TC-2216 Tebanicline UB-165 Varenicline WAY-317,538

Convulsants

Anatoxin-a Bicuculline DMCM Flurothyl Gabazine Pentetrazol Picrotoxin Strychnine Thujone

Eugeroics

Adrafinil Armodafinil CRL-40,940 CRL-40,941 Fluorenol JZ-IV-10 Modafinil

Oxazolines

4-Methylaminorex Aminorex Clominorex Cyclazodone Fenozolone Fluminorex Pemoline Thozalinone

Phenethylamines

1-(4-Methylphenyl)-2-aminobutane 1-Methylamino-1-(3,4-methylenedioxyphenyl)propane 2-Fuoroamphetamine 2-Fuoromethamphetamine 2-OH-PEA 2-Phenyl-3-aminobutane 2,3-MDA 3-Fuoroamphetamine 3-Fluoroethamphetamine 3-Fluoromethcathinone 3-Methoxyamphetamine 3-Methylamphetamine 3,4-DMMC 4-BMC 4-CMC 4-Ethylamphetamine 4-Fluoroamphetamine 4-Fluoromethamphetamine 4-MA 4-Methylbuphedrone 4-Methylcathinone 4-MMA 4-Methylpentedrone 4-MTA 6-FNE AL-1095 Alfetamine a-Ethylphenethylamine Amfecloral Amfepentorex Amfepramone Amidephrine 2-Amino-1,2-dihydronaphthalene 2-Aminoindane 5-(2-Aminopropyl)indole 2-Aminotetralin Acridorex Amphetamine
Amphetamine
(Dextroamphetamine, Levoamphetamine) Amphetaminil Arbutamine β-Methylphenethylamine β-Phenylmethamphetamine Benfluorex Benzedrone Benzphetamine BDB BOH 3-Benzhydrylmorpholine BPAP Buphedrone Bupropion Butylone Camfetamine Cathine Cathinone Chlorphentermine Cilobamine Cinnamedrine Clenbuterol Clobenzorex Cloforex Clortermine Cypenamine D-Deprenyl Denopamine Dimethoxyamphetamine Dimethylamphetamine Dimethylcathinone Dobutamine DOPA (Dextrodopa, Levodopa) Dopamine Dopexamine Droxidopa EBDB Ephedrine Epinephrine Epinine Etafedrine Ethcathinone Ethylnorepinephrine Ethylone Etilamfetamine Etilefrine Famprofazone Fencamfamin Fencamine Fenethylline Fenfluramine
Fenfluramine
(Dexfenfluramine, Levofenfluramine) Fenproporex Feprosidnine Flephedrone Fludorex Formetorex Furfenorex Gepefrine Hexapradol Hexedrone HMMA Hordenine 4-Hydroxyamphetamine 5-Iodo-2-aminoindane Ibopamine IMP Indanylamphetamine Iofetamine Isoetarine Isoethcathinone Isoprenaline L-Deprenyl (Selegiline) Lefetamine Lisdexamfetamine Lophophine MBDB MDA (tenamfetamine) MDBU MDEA MDMA
MDMA
(midomafetamine) MDMPEA MDOH MDPR MDPEA Mefenorex Mephedrone Mephentermine Metanephrine Metaraminol Mesocarb Methamphetamine
Methamphetamine
(Dextromethamphetamine, Levomethamphetamine) Methoxamine Methoxyphenamine MMA Methcathinone Methedrone Methoxyphenamine Methylenedioxycathinone Methylone Mexedrone MMDA MMDMA MMMA Morforex N,alpha-Diethylphenylethylamine N-Ethylbuphedrone N-Ethylhexedrone N,N-Dimethylphenethylamine Naphthylamphetamine Nisoxetine Norepinephrine Norfenefrine Norfenfluramine Normetanephrine L-Norpseudoephedrine Octopamine (drug) Orciprenaline Ortetamine Oxifentorex Oxilofrine PBA PCA PCMA PHA Pentorex Pentedrone Pentylone Phenatine Phenpromethamine Phentermine Phenylalanine Phenylephrine Phenylpropanolamine Pholedrine PIA PMA PMEA PMMA PPAP Phthalimidopropiophenone Prenylamine Propylamphetamine Pseudoephedrine Ropinirole Salbutamol
Salbutamol
(Levosalbutamol) Sibutramine Solriamfetol Synephrine Theodrenaline Tiflorex Tranylcypromine Tyramine Tyrosine Xylopropamine Zylofuramine

Phenylmorpholines

3-Fluorophenmetrazine Fenbutrazate Fenmetramide G-130 Manifaxine Morazone Morforex Oxaflozane PD-128,907 Phendimetrazine Phenmetrazine 2-Phenyl-3,6-dimethylmorpholine Pseudophenmetrazine Radafaxine

Piperazines

2C-B-BZP 3C-PEP BZP CM156 DBL-583 GBR-12783 GBR-12935 GBR-13069 GBR-13098 GBR-13119 MeOPP MBZP oMPP Vanoxerine

Piperidines

1-Benzyl-4-(2-(diphenylmethoxy)ethyl)piperidine 2-Benzylpiperidine 2-Methyl-3-phenylpiperidine 3,4-Dichloromethylphenidate 4-Benzylpiperidine 4-Fluoromethylphenidate 4-Methylmethylphenidate Desoxypipradrol Difemetorex Diphenylpyraline Ethylnaphthidate Ethylphenidate Methylnaphthidate Isopropylphenidate Methylphenidate
Methylphenidate
(Dexmethylphenidate) Nocaine Phacetoperane Pipradrol Propylphenidate SCH-5472

Pyrrolidines

2-Diphenylmethylpyrrolidine 5-DBFPV α-PPP α-PBP α-PHP α-PVP α-PVT Diphenylprolinol DMPVP FPOP FPVP MDPPP MDPBP MPBP MPHP MPPP MOPVP MOPPP Indapyrophenidone MDPV Naphyrone PEP Picilorex Prolintane Pyrovalerone

Racetams

Oxiracetam Phenylpiracetam Phenylpiracetam
Phenylpiracetam
hydrazide

Tropanes

4-fluorotropacocaine 4'-Fluorococaine Altropane
Altropane
(IACFT) Brasofensine CFT (WIN 35,428) β-CIT (RTI-55) Cocaethylene Cocaine Dichloropane
Dichloropane
(RTI-111) Difluoropine FE-β-CPPIT FP-β-CPPIT Ioflupane (123I) Norcocaine PIT PTT RTI-31 RTI-32 RTI-51 RTI-112 RTI-113 RTI-120 RTI-121
RTI-121
(IPCIT) RTI-126 RTI-150 RTI-177 RTI-229 RTI-336 RTI-354 RTI-371 RTI-386 Salicylmethylecgonine Tesofensine Troparil
Troparil
(β-CPT, WIN 35,065-2) Tropoxane WF-23 WF-33

Tryptamines

4-HO-αMT 4-Methyl-αET 4-Methyl-αMT 5-Chloro-αMT 5-Fluoro-αMT 5-MeO-αET 5-MeO-αMT 5-MeO-DIPT 6-Fluoro-αMT 7-Methyl-αET αET αMT

Others

2-MDP 3,3-Diphenylcyclobutanamine Amfonelic acid Amineptine Amiphenazole Atipamezole Atomoxetine Bemegride Benzydamine BTQ BTS 74,398 Centanafadine Ciclazindol Clofenciclan Cropropamide Crotetamide D-161 Desipramine Diclofensine Dimethocaine Efaroxan Etamivan Fenisorex Fenpentadiol Gamfexine Gilutensin GSK1360707F GYKI-52895 Hexacyclonate Idazoxan Indanorex Indatraline JNJ-7925476 Lazabemide Leptacline Lomevactone LR-5182 Mazindol Meclofenoxate Medifoxamine Mefexamide Methamnetamine Methastyridone Methiopropamine Naphthylaminopropane Nefopam Nikethamide Nomifensine O-2172 Oxaprotiline PNU-99,194 PRC200-SS Rasagiline Rauwolscine Rubidium chloride Setazindol Tametraline Tandamine Thiopropamine Thiothinone Trazium UH-232 Yohimbine

ATC code: N06B

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Purine receptor
Purine receptor
modulators

Receptor (ligands)

P0 (adenine)

Agonists: 8-Aminoadenine Adenine

P1 (adenosine)

Agonists: 2-(1-Hexynyl)-N-methyladenosine 2-Cl-IB-MECA 2'-MeCCPA 4'-O-β-D-Glucosyl-9-O-(6''-deoxysaccharosyl)olivil 5'-N-ethylcarboxamidoadenosine Adenosine ADP AMP Apadenoson ATL-146e ATP BAY 60–6583 Binodenoson Capadenoson CCPA CGS-21680 CP-532,903 Evodenoson GR 79236 LUF-5835 LUF-5845 N6-Cyclopentyladenosine Namodenoson Neladenoson dalanate Piclidenoson Regadenoson SDZ WAG 994 Selodenoson Sonedenoson Tecadenoson UK-432,097

Antagonists: 8-Chlorotheophylline 8-Phenyl-1,3-dipropylxanthine 8-Phenyltheophylline Acefylline Aminophylline ATL-444 Bamifylline Cafedrine Caffeine Caffeine
Caffeine
citrate Cartazolate CGH-2466 CGS-15943 Choline theophyllinate CPX CVT-6883 Dimethazan DMPX DPCPX Dyphylline Enprofylline Etazolate Fenethylline IBMX Isovaleric acid Istradefylline KF-26777 MRE3008F20 MRS-1220 MRS-1334 MRS-1706 MRS-1754 MRS-3777 Paraxanthine Pentoxifylline Preladenant Propentofylline Proxyphylline PSB-10 PSB-11 PSB-36 PSB-603 PSB-788 PSB-1115 Reversine Rolofylline SCH-442,416 SCH-58261 Theacrine Theobromine Theodrenaline Theophylline Tozadenant Tracazolate VUF-5574 ZM-241,385

P2 (nucleotide)

P2X (ATP)

Agonists: 2-Me-SATP α,β-Me-ATP Adenosine ADP AMP Ap4A Ap5A ATP ATPγS BzATP Cibacron blue CTP D-β,γ-Me-ATP GTP HT-AMP Ivermectin L-β,γ-Me-ATP MRS-2219 PAPET-ATP UTP Zinc

Antagonists: 5-BDBD A-317491 A-438079 A-740003 A-804598 A-839977 AF-353 AZ-10606120 AZ-11645373 BBG Calcium Calmidazolium Chelerythrine Copper Emodin
Emodin
(Rheum officinale) Evans Blue GW-791343 HMA Ip5I isoPPADS JNJ-47965567 KN-04 KN-62 Magnesium MRS-2159 NF-023 NF-110 NF-157 NF-279 NF-449 Opiranserin (VVZ-149) Oxidized-ATP Phenol Red Phenolphthalein PPADS PPNDS PSB-12062 Puerarin
Puerarin
(Radix puerariae) Purotoxin 1 RB-2 Ro 0437626 Ro 51 RO-3 Sodium ferulate
Sodium ferulate
(Angelica sinensis, Ligusticum wallichii) Suramin TC-P 262 Tetramethylpyrazine
Tetramethylpyrazine
(ligustrazine) (Ligusticum wallichii) TNP-ATP Zinc

P2Y

Agonists: 2-Me-SADP 2-Me-SATP 2-Thio-UTP 5-Br-UDP 5-OMe-UDP α,β-Me-ATP Adenosine ADP ADPβS Ap3A AR-C 67085MX ATP ATPγS CTP dATP Denufosol Diquafosol IDP ITP INS-365 INS-37217 MRS-2365 MRS-2690 MRS-2693 MRS-2768 MRS-2957 MRS-4062 NF-546 PAPET-ATP PSB-0474 PSB-1114 UDP UDPβS UDP-galactose UDP-glucose UDP-N-acetylglucosamine Up3U UTP UTPγS

Antagonists: 2-Me-SAMP A3P5PS AMPαS Ap4A AR-C 66096 AR-C 67085MX AR-C 69931MX AR-C 118925XX ATP BzATP C1330-7 Cangrelor Clopidogrel Elinogrel Ip5I MRS-2179 MRS-2211 MRS-2279 MRS-2395 MRS-2500 MRS-2578 NF-157 NF-340 PIT PPADS Prasugrel PSB-0739 RB-2 Regrelor Suramin Ticagrelor Ticlopidine UDP

Transporter (blockers)

CNTs

6-Hydroxy-7-methoxyflavone Adenosine dMeThPmR Estradiol KGO-2142 KGO-2173 MeThPmR Phloridzin Progesterone

ENTs

Barbiturates Benzodiazepines Cilostazol Dilazep Dipyridamole Estradiol Ethanol Hexobendine NBMPR Pentoxifylline Progesterone Propentofylline

PMAT

Decynium-22

Enzyme (inhibitors)

XO

Allopurinol Amflutizole Benzbromarone Caffeic acid Cinnamaldehyde Cinnamomum osmophloeum Febuxostat Myo-inositol Kaempferol Myricetin Niraxostat Oxipurinol Phytic acid Pistacia integerrima Propolis Quercetin Tisopurine Topiroxostat

Others

Aminopterin Azathioprine Methotrexate Mycophenolic acid Pemetrexed Pralatrexate Many others

Others

Precursors: Adenine Adenosine AMP ADP ATP Cytosine Cytidine CMP CDP CTP Guanine Guanosine GMP GDP GTP Hypoxanthine Inosine IMP IDP ITP Ribose Uracil Uridine UMP UDP UTP

Others: Chrysophanol
Chrysophanol
(rhubarb)

See also: Receptor/signaling modulators

v t e

Phosphodiesterase inhibitors

PDE1

MMPX SCH-51866 Vinpocetine

PDE2

BAY 60-7550 Carbazeran EHNA Oxindole PDP

PDE3

Adibendan Amrinone
Amrinone
(inamrinone) Anagrelide Benafentrine Bucladesine Carbazeran Cilostamide Cilostazol Enoximone Imazodan KMUP-1 Meribendan Milrinone Olprinone Parogrelil Pimobendan Pumafentrine Quazinone RPL-554 Siguazodan Trequinsin Vesnarinone Zardaverine

PDE4

Apremilast Arofylline Atizoram Benafentrine Catramilast CC-1088 CDP-840 CGH-2466 Cilomilast Cipamfylline Crisaborole Denbutylline Drotaverine Etazolate Filaminast Glaucine HT-0712 ICI-63197 Indimilast Irsogladine Lavamilast Lirimilast Luteolin Mesembrenone Mesembrine Mesopram Oglemilast Piclamilast Pumafentrine Revamilast Ro 20-1724 Roflumilast Rolipram Ronomilast RPL-554 RS-25344 Tetomilast Tofimilast YM-976 Zardaverine

PDE5

Acetildenafil Aildenafil Avanafil Beminafil Benzamidenafil Dasantafil Icariin Gisadenafil Homosildenafil Lodenafil Mirodenafil MY-5445 Nitrosoprodenafil Norcarbodenafil SCH-51866 Sildenafil Sulfoaildenafil T-0156 Tadalafil Udenafil Vardenafil

PDE7

BRL-50481

PDE9

BAY 73-6691 PF-04447943

PDE10

Balipodect Mardepodect Papaverine TC-E 5005 Tofisopam

PDE11

BC11-38

Non-selective

Aminophylline Caffeine Choline theophyllinate CPX Dipyridamole Doxofylline Enprofylline Ibudilast IBMX Luteolin Paraxanthine Pentoxifylline Propentofylline Theobromine Theophylline Zaprinast

Unsorted

Diazepam Diprophylline DPCPX Furafylline Lisofylline MDL-12330A Moxaverine Oxagrelate Pentifylline Proxyphylline Quercetin Satigrel Tolafentrine Trapidil

See also: Receptor/si

.