Theobromine

Details:

Chemical Properties of Theobromine

Cas No.	83-67-0
PubChem ID	5429	Appearance	White-beige powder
Formula	C7H8N4O2	M.Wt	180.16
Type of Compound	Alkaloids	Storage	Desiccate at -20°C
Synonyms	3,7-Dimethylxanthine
Solubility	DMSO : 6 mg/mL (33.30 mM; Need ultrasonic)
Chemical Name	3,7-dimethylpurine-2,6-dione
SMILES	CN1C=NC2=C1C(=O)NC(=O)N2C
Standard InChIKey	YAPQBXQYLJRXSA-UHFFFAOYSA-N
Standard InChI	InChI=1S/C7H8N4O2/c1-10-3-8-5-4(10)6(12)9-7(13)11(5)2/h3H,1-2H3,(H,9,12,13)
General tips	For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging	1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment.
Shipping Condition	Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Source of Theobromine

1 Cola sp. 2 Ilex sp. 3 Paullinia sp. 4 Theobroma sp.

Biological Activity of Theobromine

Description	Theobromine is a xanthine alkaloid widely consumed as stimulants and snacks in coffee and cocoa based foods, it may form the basis for a new class of antitussive drugs. Theobromine has antioxidants and also capable of prooxidant action, it may have therapeutic potential for diabetic nephropathy, by reducing kidney ECM accumulation in diabetic. It can inhibit adenosine receptor A1 (AR1) signaling.
Targets	PARP | AMPK | TGF-β/Smad | LDL
In vitro	Antioxidant and prooxidant properties of caffeine, theobromine and xanthine.[Pubmed: 12960921] Med Sci Monit. 2003 Sep;9(9):BR325-30. Caffeine, along with its catabolic products Theobromine and xanthine, is a key component of tea and coffee. These compounds are structurally similar to uric acid, a known antioxidant which is present in blood at relatively high concentrations, but also shows prooxidant activity. In view of the structural similarity between uric acid and caffeine and its metabolites, we studied the antioxidant and prooxidant properties of these compounds. METHODS AND RESULTS: Antioxidant activity was determined by measuring the quenching effect of the compounds on oxidative DNA degradation by a hydroxyl radical generating system. Prooxidant activity was studied by measuring the ability of the compounds to oxidatively degrade DNA in the presence of copper ions. Caffeine, Theobromine and xanthine have a quenching effect on the production of hydroxyl radicals, as well as on oxidative DNA breakage by hydroxyl radicals. Consistent with previous observations that many known antioxidants of plant origin are also capable of prooxidant action, the purine alkaloids also show oxidative DNA breakage in the presence of transition metal ions. CONCLUSIONS: The alkaloid caffeine and its catabolic products Theobromine and xanthine exhibit both antioxidant and prooxidant properties. The results lead to the observation that caffeine and its metabolites may also contribute to the overall antioxidant and chemopreventive properties of caffeine-bearing beverages, such as tea.
In vivo	Theobromine inhibits sensory nerve activation and cough.[Pubmed: 15548587 ] FASEB J. 2005 Feb;19(2):231-3. Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. METHODS AND RESULTS: The present study demonstrates that Theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-controlled study in man, Theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that Theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. CONCLUSIONS: These data indicate the actions of Theobromine appear to be peripherally mediated. We conclude Theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs. Effect of cocoa and theobromine consumption on serum HDL-cholesterol concentrations: a randomized controlled trial.[Pubmed: 23595874] Am J Clin Nutr. 2013 Jun;97(6):1201-9. Evidence from clinical studies has suggested that cocoa may increase high-density lipoprotein (HDL)-cholesterol concentrations. However, it is unclear whether this effect is attributable to flavonoids or Theobromine, both of which are major cocoa components. METHODS AND RESULTS: We investigated whether pure Theobromine increases serum HDL cholesterol and whether there is an interaction effect between Theobromine and cocoa. DESIGN: The study had a 2-center, double-blind, randomized, placebo-controlled, full factorial parallel design. After a 2-wk run-in period, 152 healthy men and women (aged 40-70 y) were randomly allocated to consume one 200-mL drink/d for 4 wk that contained 1) cocoa, which naturally provided 150 mg Theobromine and 325 mg flavonoids [cocoa intervention (CC)], 2) 850 mg pure Theobromine [Theobromine intervention (TB)], 3) cocoa and added Theobromine, which provided 1000 mg Theobromine and 325 mg flavonoids [Theobromine and cocoa intervention (TB+CC)], or 4) neither cocoa nor Theobromine (placebo). Blood lipids and apolipoproteins were measured at the start and end of interventions. RESULTS: In a 2-factor analysis, there was a significant main effect of the TB (P < 0.0001) but not CC (P = 0.1288) on HDL cholesterol but no significant interaction (P = 0.3735). The TB increased HDL-cholesterol concentrations by 0.16 mmol/L (P < 0.0001). Furthermore, there was a significant main effect of the TB on increasing apolipoprotein A-I (P < 0.0001) and decreasing apolipoprotein B and LDL-cholesterol concentrations (P < 0.02). CONCLUSIONS: Theobromine independently increased serum HDL-cholesterol concentrations by 0.16 mmol/L. The lack of significant cocoa and interaction effects suggested that Theobromine may be the main ingredient responsible for the HDL cholesterol-raising effect.

Protocol of Theobromine

Animal Research

Theobromine increases NAD?/Sirt-1 activity and protects the kidney under diabetic conditions.[Pubmed: 25411384] Am J Physiol Renal Physiol. 2015 Feb 1;308(3):F209-25. Reduction in sirtuin 1 (Sirt-1) is associated with extracellular matrix (ECM) accumulation in the diabetic kidney. Theobromine may reduce kidney ECM accumulation in diabetic rats. METHODS AND RESULTS: In the current study, we aimed to unravel, under diabetic conditions, the mechanism of kidney ECM accumulation induced by a reduction in Sirt-1 and the effect of Theobromine in these events. In vitro, we used immortalized human mesangial cells (iHMCs) exposed to high glucose (HG; 30 mM), with or without small interfering RNA for NOX4 and Sirt-1. In vivo, spontaneously hypertensive rats (SHR) were rendered diabetic by means of streptozotocin and studied after 12 wk. The effects of treatment with Theobromine were investigated under both conditions. HG leads to a decrease in Sirt-1 activity and NAD(+) levels in iHMCs. Sirt-1 activity could be reestablished by treatment with NAD(+), silencing NOX4, and poly (ADP-ribose) polymerase-1 (PARP-1) blockade, or with Theobromine. HG also leads to a low AMP/ATP ratio, acetylation of SMAD3, and increased collagen IV, which is prevented by Theobromine. Sirt-1 or AMPK blockade abolished these effects of Theobromine. In diabetic SHR, Theobromine prevented increases in albuminuria and kidney collagen IV, reduced AMPK, elevated NADPH oxidase activity and PARP-1, and reduced NAD(+) levels and Sirt-1 activity. CONCLUSIONS: These results suggest that in diabetes mellitus, Sirt-1 activity is reduced by PARP-1 activation and NAD(+) depletion due to low AMPK, which increases NOX4 expression, leading to ECM accumulation mediated by transforming growth factor (TGF)-β1 signaling. It is suggested that Sirt-1 activation by Theobromine may have therapeutic potential for diabetic nephropathy.

Structure Identification

Mutat Res. 1975;32(2):169-78. Theobromine and theophylline.[Pubmed: 765793] Theobromine and theophylline have a limited therapeutic use and in addition they occur in plants used in the preparation of a number of widely consumed drinks. Thus most of the population must be exposed to both compounds. METHODS AND RESULTS: Chromosome abnormalities are caused by both Theobromine and theophylline in plant cells and in mammalian cells in culture, and both have anti-mitotic activity. While they are fairly potent mutagens in Escherichia coli and other lower organisms the rather scanty available evidence suggests that they are not mutagenic in mammals. The difference in mutagenic activity may be due to the reported inability of E. coli to demethylate these compounds, a process which occurs readily in mammals including man. CONCLUSIONS: The structure-activity relationships of these compounds are complex but the available evidence suggests that methylation at position 1 is the most important for both mutagenic activity and the anti-mitotic effect while methylation at position 3 is of most importance in the action on chromosomes.

Preparing Stock Solutions of Theobromine

	1 mg	5 mg	10 mg	20 mg	25 mg
1 mM	5.5506 mL	27.7531 mL	55.5062 mL	111.0124 mL	138.7655 mL
5 mM	1.1101 mL	5.5506 mL	11.1012 mL	22.2025 mL	27.7531 mL
10 mM	0.5551 mL	2.7753 mL	5.5506 mL	11.1012 mL	13.8766 mL
50 mM	0.111 mL	0.5551 mL	1.1101 mL	2.2202 mL	2.7753 mL
100 mM	0.0555 mL	0.2775 mL	0.5551 mL	1.1101 mL	1.3877 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

References on Theobromine

Theobromine inhibits sensory nerve activation and cough.[Pubmed:15548587]

FASEB J. 2005 Feb;19(2):231-3.

Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that Theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-controlled study in man, Theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that Theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. These data indicate the actions of Theobromine appear to be peripherally mediated. We conclude Theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs.

Effect of cocoa and theobromine consumption on serum HDL-cholesterol concentrations: a randomized controlled trial.[Pubmed:23595874]

Am J Clin Nutr. 2013 Jun;97(6):1201-9.

BACKGROUND: Evidence from clinical studies has suggested that cocoa may increase high-density lipoprotein (HDL)-cholesterol concentrations. However, it is unclear whether this effect is attributable to flavonoids or Theobromine, both of which are major cocoa components. OBJECTIVES: We investigated whether pure Theobromine increases serum HDL cholesterol and whether there is an interaction effect between Theobromine and cocoa. DESIGN: The study had a 2-center, double-blind, randomized, placebo-controlled, full factorial parallel design. After a 2-wk run-in period, 152 healthy men and women (aged 40-70 y) were randomly allocated to consume one 200-mL drink/d for 4 wk that contained 1) cocoa, which naturally provided 150 mg Theobromine and 325 mg flavonoids [cocoa intervention (CC)], 2) 850 mg pure Theobromine [Theobromine intervention (TB)], 3) cocoa and added Theobromine, which provided 1000 mg Theobromine and 325 mg flavonoids [Theobromine and cocoa intervention (TB+CC)], or 4) neither cocoa nor Theobromine (placebo). Blood lipids and apolipoproteins were measured at the start and end of interventions. RESULTS: In a 2-factor analysis, there was a significant main effect of the TB (P < 0.0001) but not CC (P = 0.1288) on HDL cholesterol but no significant interaction (P = 0.3735). The TB increased HDL-cholesterol concentrations by 0.16 mmol/L (P < 0.0001). Furthermore, there was a significant main effect of the TB on increasing apolipoprotein A-I (P < 0.0001) and decreasing apolipoprotein B and LDL-cholesterol concentrations (P < 0.02). CONCLUSIONS: Theobromine independently increased serum HDL-cholesterol concentrations by 0.16 mmol/L. The lack of significant cocoa and interaction effects suggested that Theobromine may be the main ingredient responsible for the HDL cholesterol-raising effect. This trial was registered at clinicaltrials.gov as NCT01481389.

Theobromine and theophylline.[Pubmed:765793]

Mutat Res. 1975;32(2):169-78.

Theobromine and theophylline have a limited therapeutic use and in addition they occur in plants used in the preparation of a number of widely consumed drinks. Thus most of the population must be exposed to both compounds. Chromosome abnormalities are caused by both Theobromine and theophylline in plant cells and in mammalian cells in culture, and both have anti-mitotic activity. While they are fairly potent mutagens in Escherichia coli and other lower organisms the rather scanty available evidence suggests that they are not mutagenic in mammals. The difference in mutagenic activity may be due to the reported inability of E. coli to demethylate these compounds, a process which occurs readily in mammals including man. The structure-activity relationships of these compounds are complex but the available evidence suggests that methylation at position 1 is the most important for both mutagenic activity and the anti-mitotic effect while methylation at position 3 is of most importance in the action on chromosomes.

Antioxidant and prooxidant properties of caffeine, theobromine and xanthine.[Pubmed:12960921]

Med Sci Monit. 2003 Sep;9(9):BR325-30.

BACKGROUND: Caffeine, along with its catabolic products Theobromine and xanthine, is a key component of tea and coffee. These compounds are structurally similar to uric acid, a known antioxidant which is present in blood at relatively high concentrations, but also shows prooxidant activity. In view of the structural similarity between uric acid and caffeine and its metabolites, we studied the antioxidant and prooxidant properties of these compounds. MATERIAL/METHODS: Antioxidant activity was determined by measuring the quenching effect of the compounds on oxidative DNA degradation by a hydroxyl radical generating system. Prooxidant activity was studied by measuring the ability of the compounds to oxidatively degrade DNA in the presence of copper ions. RESULTS: Caffeine, Theobromine and xanthine have a quenching effect on the production of hydroxyl radicals, as well as on oxidative DNA breakage by hydroxyl radicals. Consistent with previous observations that many known antioxidants of plant origin are also capable of prooxidant action, the purine alkaloids also show oxidative DNA breakage in the presence of transition metal ions. CONCLUSIONS: The alkaloid caffeine and its catabolic products Theobromine and xanthine exhibit both antioxidant and prooxidant properties. The results lead to the observation that caffeine and its metabolites may also contribute to the overall antioxidant and chemopreventive properties of caffeine-bearing beverages, such as tea.

Theobromine increases NAD(+)/Sirt-1 activity and protects the kidney under diabetic conditions.[Pubmed:25411384]

Am J Physiol Renal Physiol. 2015 Feb 1;308(3):F209-25.

Reduction in sirtuin 1 (Sirt-1) is associated with extracellular matrix (ECM) accumulation in the diabetic kidney. Theobromine may reduce kidney ECM accumulation in diabetic rats. In the current study, we aimed to unravel, under diabetic conditions, the mechanism of kidney ECM accumulation induced by a reduction in Sirt-1 and the effect of Theobromine in these events. In vitro, we used immortalized human mesangial cells (iHMCs) exposed to high glucose (HG; 30 mM), with or without small interfering RNA for NOX4 and Sirt-1. In vivo, spontaneously hypertensive rats (SHR) were rendered diabetic by means of streptozotocin and studied after 12 wk. The effects of treatment with Theobromine were investigated under both conditions. HG leads to a decrease in Sirt-1 activity and NAD(+) levels in iHMCs. Sirt-1 activity could be reestablished by treatment with NAD(+), silencing NOX4, and poly (ADP-ribose) polymerase-1 (PARP-1) blockade, or with Theobromine. HG also leads to a low AMP/ATP ratio, acetylation of SMAD3, and increased collagen IV, which is prevented by Theobromine. Sirt-1 or AMPK blockade abolished these effects of Theobromine. In diabetic SHR, Theobromine prevented increases in albuminuria and kidney collagen IV, reduced AMPK, elevated NADPH oxidase activity and PARP-1, and reduced NAD(+) levels and Sirt-1 activity. These results suggest that in diabetes mellitus, Sirt-1 activity is reduced by PARP-1 activation and NAD(+) depletion due to low AMPK, which increases NOX4 expression, leading to ECM accumulation mediated by transforming growth factor (TGF)-beta1 signaling. It is suggested that Sirt-1 activation by Theobromine may have therapeutic potential for diabetic nephropathy.

Description

Theobromine is a methylxanthine found in cacao beans which can inhibit adenosine receptor A1 (AR1) signaling.

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