Paraxanthine
Chemical compound From Wikipedia, the free encyclopedia
Paraxanthine, also known as 1,7-dimethylxanthine, is an isomer 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.
| |
 | |
| 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 |
PubChem CID |
|
| UNII | |
CompTox Dashboard (EPA) |
|
| |
| |
| 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).
| |
Production and metabolism
Summarize
Perspective
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
Summarize
Perspective
 | This section needs more reliable medical references for verification or relies too heavily on primary sources. (November 2021) |  |
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).
| Plasma Half-Life
(t1/2; hr) |
Volume of Distribution
(Vss,unbound; l/kg) |
Plasma Clearance
(CL; ml/min/kg) | |
|---|---|---|---|
| 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 |
Uses
Paraxanthine is a phosphodiesterase type 9 (PDE9) inhibitor and it is sold as a research molecule for this same purpose.[21]
Toxicity
Summarize
Perspective
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]
References
External links
Wikiwand - on
Seamless Wikipedia browsing. On steroids.