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Identification
NameTheobromine
Accession NumberDB01412
Typesmall molecule
Groupsapproved
Description

3,7-Dimethylxanthine. The principle alkaloid in Theobroma cacao (the cacao bean) and other plants. A xanthine alkaloid that is used as a bronchodilator and as a vasodilator. It has a weaker diuretic activity than theophylline and is also a less powerful stimulant of smooth muscle. It has practically no stimulant effect on the central nervous system. It was formerly used as a diuretic and in the treatment of angina pectoris and hypertension. (From Martindale, The Extra Pharmacopoeia, 30th ed, pp1318-9)

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand namesNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number83-67-0
WeightAverage: 180.164
Monoisotopic: 180.06472552
Chemical FormulaC7H8N4O2
InChI KeyYAPQBXQYLJRXSA-UHFFFAOYSA-N
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)
IUPAC Name
3,7-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione
SMILES
CN1C=NC2=C1C(=O)NC(=O)N2C
Mass Specshow(8.9 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassImidazopyrimidines
SubclassPurines and Purine Derivatives
Direct parentXanthines
Alternative parentsPurinones; Pyrimidones; N-substituted Imidazoles; Polyamines
Substituentspyrimidone; pyrimidine; n-substituted imidazole; imidazole; azole; polyamine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the xanthines. These are purine derivatives with a ketone group conjugated at carbons 2 and 6 of the purine moiety.
Pharmacology
Indicationtheobromine is used as a vasodilator, a diuretic, and heart stimulant. And similar to caffeine, it may be useful in management of fatigue and orthostatic hypotension.
PharmacodynamicsTheobromine, a xanthine derivative like caffeine and the bronchodilator theophylline, is used as a CNS stimulant, mild diuretic, and respiratory stimulant (in neonates with apnea of prematurity).
Mechanism of actionTheobromine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate. This action was previously believed to be due primarily to increased intracellular cyclic 3′,5′-adenosine monophosphate (cyclic AMP) following inhibition of phosphodiesterase, the enzyme that degrades cyclic AMP. It is now thought that xanthines such as caffeine and theobromine act as antagonist at adenosine-receptors within the plasma membrane of virtually every cell. As adenosine acts as an autocoid, inhibiting the release of neurotransmitters from presynaptic sites but augmenting the actions of norepinephrine or angiotensin, antagonism of adenosine receptors promotes neurotransmitter release. This explains the stimulatory effects of xanthine derivatives such as theobromine and caffeine. Blockade of the adenosine A1 receptor in the heart leads to the accelerated, pronounced "pounding" of the heart upon caffeine intake.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organismsNot Available
Pathways
PathwayCategorySMPDB ID
Caffeine MetabolismMetabolicSMP00028
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9902
Caco-2 permeable + 0.6172
P-glycoprotein substrate Non-substrate 0.7281
P-glycoprotein inhibitor I Non-inhibitor 0.8939
P-glycoprotein inhibitor II Non-inhibitor 0.911
Renal organic cation transporter Non-inhibitor 0.8807
CYP450 2C9 substrate Non-substrate 0.7738
CYP450 2D6 substrate Non-substrate 0.9117
CYP450 3A4 substrate Non-substrate 0.5974
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.9933
CYP450 2D6 substrate Non-inhibitor 0.9827
CYP450 2C19 substrate Non-inhibitor 0.9895
CYP450 3A4 substrate Non-inhibitor 0.9616
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9956
Ames test Non AMES toxic 0.9132
Carcinogenicity Non-carcinogens 0.9447
Biodegradation Ready biodegradable 0.5942
Rat acute toxicity 2.7898 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8819
hERG inhibition (predictor II) Non-inhibitor 0.8927
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Solution / dropsOral
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point357 °CPhysProp
water solubility330 mg/L (at 25 °C)YALKOWSKY,SH & HE,Y (2003)
logP-0.78HANSCH,C ET AL. (1995)
pKa9.9KORTUM,G ET AL (1961)
Predicted Properties
PropertyValueSource
water solubility9.74e+00 g/lALOGPS
logP-0.46ALOGPS
logP-0.77ChemAxon
logS-1.3ALOGPS
pKa (strongest acidic)9.28ChemAxon
pKa (strongest basic)-0.91ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count1ChemAxon
polar surface area67.23ChemAxon
rotatable bond count0ChemAxon
refractivity44.93ChemAxon
polarizability16.85ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraGC-MSMS/MSLC-MS1D NMR2D NMR
References
Synthesis Reference

Misako Mizuno, Hiroshi Ashihara, Kouichi Mizuno, Tatsuhito Fujimura, “CAMELLIA SINENSIS GENE ENCODING A CAFFEINE SYNTHESIS ASSOCIATED N-METHYL TRANSFERASE WITH 7-METHYLXANTHINE N3 METHYL TRANSFERASE, THEOBROMINE N1 METHYL TRANSFERASE, AND PARAXANTHINE N3 METHYL TRANSFERASE ACTIVITIES AND USE THEREOF.” U.S. Patent US06930227, issued August 16, 2005.

US06930227
General Reference
  1. Usmani OS, Belvisi MG, Patel HJ, Crispino N, Birrell MA, Korbonits M, Korbonits D, Barnes PJ: Theobromine inhibits sensory nerve activation and cough. FASEB J. 2005 Feb;19(2):231-3. Epub 2004 Nov 17. Pubmed
  2. Slattery ML, West DW: Smoking, alcohol, coffee, tea, caffeine, and theobromine: risk of prostate cancer in Utah (United States). Cancer Causes Control. 1993 Nov;4(6):559-63. Pubmed
External Links
ResourceLink
KEGG CompoundC07480
PubChem Compound5429
PubChem Substance46508574
ChemSpider5236
ChEBI28946
ChEMBLCHEMBL1114
PharmGKBPA451646
Drug Product Database2236220
WikipediaTheobromine
ATC CodesC03BD01R03DA07
AHFS Codes
  • 92:02.00*
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(74.2 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Adenosine receptor A1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Adenosine receptor A1 P30542 Details

References:

  1. Chou CC, Vickroy TW: Antagonism of adenosine receptors by caffeine and caffeine metabolites in equine forebrain tissues. Am J Vet Res. 2003 Feb;64(2):216-24. Pubmed
  2. Gaytan SP, Saadani-Makki F, Bodineau L, Frugiere A, Larnicol N, Pasaro R: Effect of postnatal exposure to caffeine on the pattern of adenosine A1 receptor distribution in respiration-related nuclei of the rat brainstem. Auton Neurosci. 2006 Jun 30;126-127:339-46. Epub 2006 May 15. Pubmed
  3. Wang SJ: Caffeine facilitation of glutamate release from rat cerebral cortex nerve terminals (synaptosomes) through activation protein kinase C pathway: an interaction with presynaptic adenosine A1 receptors. Synapse. 2007 Jun;61(6):401-11. Pubmed
  4. Rieg T, Schnermann J, Vallon V: Adenosine A1 receptors determine effects of caffeine on total fluid intake but not caffeine appetite. Eur J Pharmacol. 2007 Jan 26;555(2-3):174-7. Epub 2006 Oct 25. Pubmed
  5. Mustafa S, Venkatesh P, Pasha K, Mullangi R, Srinivas NR: Altered intravenous pharmacokinetics of topotecan in rats with acute renal failure (ARF) induced by uranyl nitrate: do adenosine A1 antagonists (selective/non-selective) normalize the altered topotecan kinetics in ARF? Xenobiotica. 2006 Dec;36(12):1239-58. Pubmed
  6. Listos J, Malec D, Fidecka S: Adenosine receptor antagonists intensify the benzodiazepine withdrawal signs in mice. Pharmacol Rep. 2006 Sep-Oct;58(5):643-51. Pubmed
  7. Fisone G, Borgkvist A, Usiello A: Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci. 2004 Apr;61(7-8):857-72. Pubmed
  8. Daly JW, Jacobson KA, Ukena D: Adenosine receptors: development of selective agonists and antagonists. Prog Clin Biol Res. 1987;230:41-63. Pubmed

2. Adenosine receptor A2a

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Adenosine receptor A2a P29274 Details

References:

  1. Chou CC, Vickroy TW: Antagonism of adenosine receptors by caffeine and caffeine metabolites in equine forebrain tissues. Am J Vet Res. 2003 Feb;64(2):216-24. Pubmed
  2. Riksen NP, Franke B, van den Broek P, Smits P, Rongen GA: The 1976C>T polymorphism in the adenosine A2A receptor gene does not affect the vasodilator response to adenosine in humans in vivo. Pharmacogenet Genomics. 2007 Jul;17(7):551-4. Pubmed
  3. Zhao G, Messina E, Xu X, Ochoa M, Sun HL, Leung K, Shryock J, Belardinelli L, Hintze TH: Caffeine attenuates the duration of coronary vasodilation and changes in hemodynamics induced by regadenoson (CVT-3146), a novel adenosine A2A receptor agonist. J Cardiovasc Pharmacol. 2007 Jun;49(6):369-75. Pubmed
  4. Cornelis MC, El-Sohemy A, Campos H: Genetic polymorphism of the adenosine A2A receptor is associated with habitual caffeine consumption. Am J Clin Nutr. 2007 Jul;86(1):240-4. Pubmed
  5. Fisone G, Borgkvist A, Usiello A: Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci. 2004 Apr;61(7-8):857-72. Pubmed
  6. Daly JW, Jacobson KA, Ukena D: Adenosine receptors: development of selective agonists and antagonists. Prog Clin Biol Res. 1987;230:41-63. Pubmed

3. cAMP-specific 3',5'-cyclic phosphodiesterase 4B

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
cAMP-specific 3',5'-cyclic phosphodiesterase 4B Q07343 Details

References:

  1. Essayan DM: Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol. 2001 Nov;108(5):671-80. Pubmed
  2. Fisone G, Borgkvist A, Usiello A: Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci. 2004 Apr;61(7-8):857-72. Pubmed
  3. Daly JW: Caffeine analogs: biomedical impact. Cell Mol Life Sci. 2007 Aug;64(16):2153-69. Pubmed
  4. 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 (Sao Paulo). 2008 Jun;63(3):321-8. Pubmed

Enzymes

1. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  2. Gates S, Miners JO: Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism. Br J Clin Pharmacol. 1999 Mar;47(3):299-305. Pubmed

2. Cytochrome P450 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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Drug created on July 17, 2007 06:41 / Updated on September 16, 2013 17:14