T3DB: Theophylline

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Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (9)XML

Targets (9)

Record Information

Version

2.0

Creation Date

2014-09-11 05:16:16 UTC

Update Date

2014-12-24 20:26:57 UTC

Accession Number

T3D4780

Identification

Common Name

Theophylline

Class

Small Molecule

Description

A methylxanthine derivative from tea with diuretic, smooth muscle relaxant, bronchial dilation, cardiac and central nervous system stimulant activities. Mechanistically, theophylline acts as a phosphodiesterase inhibitor, adenosine receptor blocker, and histone deacetylase activator. Theophylline is marketed under several brand names such as Uniphyl and Theochron, and it is indicated mainly for asthma, bronchospasm, and COPD.

Compound Type

Amide
Bronchodilator Agent
Drug
Food Toxin
Metabolite
Muscle Relaxant, Respiratory
Organic Compound
Phosphodiesterase Inhibitor
Purinergic P1 Receptor Antagonist
Synthetic Compound
Vasodilator Agent

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
1,3-dimethyl-7H-purine-2,6-dione
1,3-Dimethylxanthine
Accurbron
Acet-theocin
Aerolate
Aerolate III
Aerolate SR
Aminophylline
Aquaphyllin
Armophylline
Asbron
Asmax
Austyn
Bronkodyl
Bronkodyl SR
Choledyl SA
Constant-T
Diphyllin
Doraphyllin
Duraphyl
Dyspne-Inhal
Elixex
Elixicon
Elixomin
Elixophyllin
Elixophyllin SR
Elixophylline
Euphylline
Euphylong
Labid
Lanophyllin
Liquophylline
Liquorice
Maphylline
Medaphyllin
Nuelin
Optiphyllin
Parkophyllin
Pseudotheophylline
Quibron T/SR
Quibron-T
Quibron-T/Sr
Respbid
Slo-Bid
Slo-Phyllin
Solosin
Somophyllin-Crt
Somophyllin-DF
Somophyllin-T
Spophyllin retard
Sustaire
Synophylate
Synophylate-L.A. Cenules
T-Phyl
Tefamin
Teofilina
Teofyllamin
Teolair
Theacitin
Theal tabl.
Theal tablets
Theo 24
Theo-24
Theo-Dur
Theo-Dur-Sprinkle
Theobid
Theobid Jr.
Theochron
Theocin
Theoclair-SR
Theoclear 80
Theoclear L.A.-130
Theoclear LA
Theoclear-200
Theoclear-80
Theocontin
Theodel
Theodur G
Theofol
Theograd
Theolair
Theolair-Sr
Theolix
Theolixir
Theona P
Theophyl
Theophyl-225
Theophyl-Sr
Theophyline
Theophyllin
Theophylline anhydrous
Theophylline(Anhydrous)
Theophylline-Sr
Theostat 80
Theovent
Uni-Dur
Unifyl
Uniphyl
Uniphyllin
Xanthium
Xantivent

Chemical Formula

C₇H₈N₄O₂

Average Molecular Mass

180.164 g/mol

Monoisotopic Mass

180.065 g/mol

CAS Registry Number

58-55-9

IUPAC Name

1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione

Traditional Name

theophylline

SMILES

CN1C2=C(N=CN2)C(=O)N(C)C1=O

InChI Identifier

InChI=1S/C7H8N4O2/c1-10-5-4(8-3-9-5)6(12)11(2)7(10)13/h3H,1-2H3,(H,8,9)

InChI Key

InChIKey=ZFXYFBGIUFBOJW-UHFFFAOYSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as xanthines. These are purine derivatives with a ketone group conjugated at carbons 2 and 6 of the purine moiety.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Imidazopyrimidines

Sub Class

Purines and purine derivatives

Direct Parent

Xanthines

Alternative Parents

Substituents

Xanthine
6-oxopurine
Purinone
Alkaloid or derivatives
Pyrimidone
Pyrimidine
Azole
Imidazole
Heteroaromatic compound
Vinylogous amide
Lactam
Urea
Azacycle
Hydrocarbon derivative
Organic oxide
Organooxygen compound
Organonitrogen compound
Organic nitrogen compound
Organopnictogen compound
Organic oxygen compound
Aromatic heteropolycyclic compound

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

dimethylxanthine (CHEBI:28177 )
Purine alkaloids (C07130 )
a small molecule (CPD-12479 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Cytoplasm
Extracellular

Biofluid Locations

Not Available

Tissue Locations

Adipose Tissue
Adrenal Medulla
Brain
Epidermis
Fibroblasts
Kidney
Liver
Muscle
Nerve Cells
Neutrophil
Pancreas
Placenta
Platelet
Skeletal Muscle
Stratum Corneum
Testes

Pathways

Name	SMPDB Link	KEGG Link
Caffeine Metabolism	SMP00028	map00232

Applications

Not Available

Biological Roles

Not Available

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	273°C
Boiling Point	Not Available
Solubility	7360 mg/L (at 25°C)
LogP	-0.02

Predicted Properties

Property	Value	Source
Water Solubility	22.9 g/L	ALOGPS
logP	-0.26	ALOGPS
logP	-0.77	ChemAxon
logS	-0.9	ALOGPS
pKa (Strongest Acidic)	7.82	ChemAxon
pKa (Strongest Basic)	-0.78	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	69.3 Å²	ChemAxon
Rotatable Bond Count	0	ChemAxon
Refractivity	44.93 m³·mol⁻¹	ChemAxon
Polarizability	16.86 Å³	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	View
GC-MS	GC-MS Spectrum - GC-MS (1 TMS)	splash10-0f79-6970000000-224461ad62a44dbdf860	JSpectraViewer \| MoNA
GC-MS	GC-MS Spectrum - EI-B (Non-derivatized)	splash10-001j-7900000000-a08735d528e738752429	JSpectraViewer \| MoNA
GC-MS	GC-MS Spectrum - CI-B (Non-derivatized)	splash10-001i-0900000000-d0882f7d959c726e7623	JSpectraViewer \| MoNA
GC-MS	GC-MS Spectrum - EI-B (Non-derivatized)	splash10-001i-9700000000-8d0e1898a6571fbca10a	JSpectraViewer \| MoNA
GC-MS	GC-MS Spectrum - GC-MS (Non-derivatized)	splash10-0f79-6970000000-224461ad62a44dbdf860	JSpectraViewer \| MoNA
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0fka-4900000000-878cab6882fd80efba3b	JSpectraViewer
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	JSpectraViewer
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)	splash10-00di-0900000000-0092516012d6a2a93b31	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)	splash10-00di-4900000000-dcf52c18a6996f412b1a	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)	splash10-00kf-9000000000-09089337909892ef44cb	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - EI-B (Unknown) , Positive	splash10-001j-7900000000-a08735d528e738752429	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - CI-B (Unknown) , Positive	splash10-001i-0900000000-d0882f7d959c726e7623	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negative	splash10-004i-0900000000-c4943571126a44bb9e5a	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negative	splash10-004i-0900000000-bc12ce29acd02fa749b8	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Negative	splash10-03k9-0900000000-d63f60043f186fbb9bc0	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Negative	splash10-070l-4900000000-d293ab2fa6199dbaf97a	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Negative	splash10-05ru-9400000000-dde4775588d52c83806f	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negative	splash10-004i-0900000000-556e382f583d610ef1f0	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negative	splash10-004i-0900000000-89e34f5158856ba33469	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Negative	splash10-03k9-0900000000-65a6897d72954e875b00	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Negative	splash10-070l-4900000000-df16604bd6c40cee8f24	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Negative	splash10-05r3-9500000000-39a721dcecc86ed95507	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Positive	splash10-001i-1900000000-e67ff7ef9a955b90eb3f	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Positive	splash10-001i-3900000000-1870952d98dbba22ace8	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Positive	splash10-00di-7900000000-dc0e9606776c43a7823f	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Positive	splash10-014j-9300000000-2c4c6490dda3ed3b563f	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Positive	splash10-014i-9000000000-26a6c0c23a465afdcde1	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Positive	splash10-01q9-1900000000-b11ca3441bb29fef1906	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Positive	splash10-0002-9400000000-63726fe0b49a9dc6ba7e	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Positive	splash10-00di-9100000000-139f765bc9b5855960c6	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Positive	splash10-00di-9000000000-88b5cb393b960973ac64	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Positive	splash10-00yi-9000000000-1ebbddce3c7133972546	JSpectraViewer \| MoNA
MS	Mass Spectrum (Electron Ionization)	splash10-00lr-9500000000-2c8464c2fe84464c207f	JSpectraViewer \| MoNA
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
2D NMR	[1H,13C] 2D NMR Spectrum	Not Available	JSpectraViewer

Toxicity Profile

Route of Exposure

Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form.

Mechanism of Toxicity

Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin.

Metabolism

Hepatic. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine. Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. Route of Elimination: Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Half Life: 8 hours

Toxicity Values

Not Available

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

3, not classifiable as to its carcinogenicity to humans. (14)

Uses/Sources

For the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, such as emphysema and chronic bronchitis.

Minimum Risk Level

Not Available

Health Effects

Not Available

Symptoms

Symptoms of overdose include seizures, arrhythmias, and GI effects.

Treatment

Not Available

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

28177

BioCyc ID

THF-GLU-N

CTD ID

Not Available

Stitch ID

Not Available

PDB ID

TEP

ACToR ID

Not Available

Wikipedia Link

Theophylline

References

Synthesis Reference

Nicolae S. Bodor, Kenneth B. Sloan, Yu-Neng Kuo, “Method for synthesizing certain selected pro-drug forms of theophylline.” U.S. Patent US4000132, issued January, 1956.

MSDS

Link

General References

Bath PM: Theophylline, aminophylline, caffeine and analogues for acute ischaemic stroke. Cochrane Database Syst Rev. 2004;(3):CD000211. [15266427 ]
Yasui K, Agematsu K, Shinozaki K, Hokibara S, Nagumo H, Yamada S, Kobayashi N, Komiyama A: Effects of theophylline on human eosinophil functions: comparative study with neutrophil functions. J Leukoc Biol. 2000 Aug;68(2):194-200. [10947063 ]
Gerbershagen MU, Fiege M, Weisshorn R, Kolodzie K, Wappler F: [Theophylline induces contractures in porcine skeletal muscle preparations with the disposition to malignant hyperthermia]. Anasthesiol Intensivmed Notfallmed Schmerzther. 2004 Mar;39(3):147-52. [15042504 ]
Mahomed AG, Theron AJ, Anderson R, Feldman C: Anti-oxidative effects of theophylline on human neutrophils involve cyclic nucleotides and protein kinase A. Inflammation. 1998 Dec;22(6):545-57. [9824770 ]
Andreas S, Reiter H, Luthje L, Delekat A, Grunewald RW, Hasenfuss G, Somers VK: Differential effects of theophylline on sympathetic excitation, hemodynamics, and breathing in congestive heart failure. Circulation. 2004 Oct 12;110(15):2157-62. Epub 2004 Oct 4. [15466632 ]
Yano Y, Yoshida M, Hoshino S, Inoue K, Kida H, Yanagita M, Takimoto T, Hirata H, Kijima T, Kumagai T, Osaki T, Tachibana I, Kawase I: Anti-fibrotic effects of theophylline on lung fibroblasts. Biochem Biophys Res Commun. 2006 Mar 17;341(3):684-90. Epub 2006 Jan 18. [16430859 ]
Mohiuddin AA, Bath FJ, Bath PM: Theophylline, aminophylline, caffeine and analogues for acute ischaemic stroke. Cochrane Database Syst Rev. 2000;(2):CD000211. [10796327 ]
Mehta R, Weinberger B, Usmani SS, Wapnir RA, Harper RG: Theophylline alters neutrophil function in preterm infants. Biol Neonate. 2002;81(3):176-81. [11937723 ]
Benoehr P, Krueth P, Bokemeyer C, Grenz A, Osswald H, Hartmann JT: Nephroprotection by theophylline in patients with cisplatin chemotherapy: a randomized, single-blinded, placebo-controlled trial. J Am Soc Nephrol. 2005 Feb;16(2):452-8. Epub 2004 Dec 8. [15590762 ]
Spoelstra FM, Berends C, Dijkhuizen B, de Monchy JG, Kauffman HF: Effect of theophylline on CD11b and L-selectin expression and density of eosinophils and neutrophils in vitro. Eur Respir J. 1998 Sep;12(3):585-91. [9762784 ]
Bailey DN: Relative binding of acetaminophen, lidocaine, phenobarbital, phenytoin, quinidine, and theophylline to human tissues in vitro. J Anal Toxicol. 1997 Jan-Feb;21(1):1-4. [9013284 ]
Teplinskaia LE, Filichkina NS, Matevosova KS: [Efficiency of treatment of uveitis with the drug superlymph]. Vestn Oftalmol. 2005 Jul-Aug;121(4):22-6. [16223038 ]
Yoshiike T, Aikawa Y, Sindhvananda J, Suto H, Nishimura K, Kawamoto T, Ogawa H: Skin barrier defect in atopic dermatitis: increased permeability of the stratum corneum using dimethyl sulfoxide and theophylline. J Dermatol Sci. 1993 Apr;5(2):92-6. [8357787 ]
International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. Adenosine receptor A2b

General Function:: G-protein coupled adenosine receptor activity
Specific Function:: Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Gene Name:: ADORA2B
Uniprot ID:: P29275
Molecular Weight:: 36332.655 Da

References

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
Philipp S, Yang XM, Cui L, Davis AM, Downey JM, Cohen MV: Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade. Cardiovasc Res. 2006 May 1;70(2):308-14. Epub 2006 Feb 23. [16545350 ]
Phelps PT, Anthes JC, Correll CC: Characterization of adenosine receptors in the human bladder carcinoma T24 cell line. Eur J Pharmacol. 2006 Apr 24;536(1-2):28-37. Epub 2006 Mar 3. [16581066 ]
Fozard JR, Baur F, Wolber C: Antagonist pharmacology of adenosine A2B receptors from rat, guinea pig and dog. Eur J Pharmacol. 2003 Aug 15;475(1-3):79-84. [12954362 ]
Holgate ST: The Quintiles Prize Lecture 2004. The identification of the adenosine A2B receptor as a novel therapeutic target in asthma. Br J Pharmacol. 2005 Aug;145(8):1009-15. [15980878 ]
Daly JW, Jacobson KA, Ukena D: Adenosine receptors: development of selective agonists and antagonists. Prog Clin Biol Res. 1987;230:41-63. [3588607 ]

Target Details

2. cAMP-specific 3',5'-cyclic phosphodiesterase 4A

General Function:: Metal ion binding
Specific Function:: Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Gene Name:: PDE4A
Uniprot ID:: P27815
Molecular Weight:: 98142.155 Da

References

Wang K, Chen JQ, Chen Z, Chen JC: Inhibition of human phosphodiesterase 4A expressed in yeast cell GL62 by theophylline, rolipram, and acetamide-45. Acta Pharmacol Sin. 2002 Nov;23(11):1013-7. [12421478 ]
Haider S: Cyclic AMP level and phosphodiesterase activity during 17alpha,20beta-dihydroxy-4-pregnen-3-one induction and theophylline inhibition of oocyte maturation in the catfish, Clarias batrachus. Comp Biochem Physiol A Mol Integr Physiol. 2003 Feb;134(2):267-74. [12547256 ]
Rickards KJ, Andrews MJ, Waterworth TH, Alexander GB, Cunningham FM: Differential effects of phosphodiesterase inhibitors on platelet activating factor (PAF)- and adenosine diphosphate (ADP)-induced equine platelet aggregation. J Vet Pharmacol Ther. 2003 Aug;26(4):277-82. [12887610 ]
Usta C, Sadan G, Tuncel B: The effect of the indomethacin on phosphodiesterase inhibitors mediated responses in isolated trachea preparations. Prostaglandins Leukot Essent Fatty Acids. 2004 Sep;71(3):137-41. [15253881 ]
Lee JM, Zemans RL, Hejazi M, Chin BB, Ladenson PW, Caturegli P: Modulation of thyroidal radioiodine uptake by theophylline. Exp Mol Pathol. 2004 Oct;77(2):116-20. [15351234 ]

Target Details

3. cGMP-inhibited 3',5'-cyclic phosphodiesterase A

General Function:: Metal ion binding
Specific Function:: Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.
Gene Name:: PDE3A
Uniprot ID:: Q14432
Molecular Weight:: 124978.06 Da

References

Rickards KJ, Andrews MJ, Waterworth TH, Alexander GB, Cunningham FM: Differential effects of phosphodiesterase inhibitors on platelet activating factor (PAF)- and adenosine diphosphate (ADP)-induced equine platelet aggregation. J Vet Pharmacol Ther. 2003 Aug;26(4):277-82. [12887610 ]
Wu BN, Lin RJ, Lo YC, Shen KP, Wang CC, Lin YT, Chen IJ: KMUP-1, a xanthine derivative, induces relaxation of guinea-pig isolated trachea: the role of the epithelium, cyclic nucleotides and K+ channels. Br J Pharmacol. 2004 Aug;142(7):1105-14. Epub 2004 Jul 5. [15237094 ]
Kajikawa S, Kigami D, Nakayama H, Doi K: Changes in submaxillary gland gene expression in F344 rats by multiple dosing of theophylline. Exp Anim. 2006 Apr;55(2):143-6. [16651698 ]

Target Details

4. Histone deacetylase 2

General Function:: Transcription factor binding
Specific Function:: Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR. Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation. Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A.
Gene Name:: HDAC2
Uniprot ID:: Q92769
Molecular Weight:: 55363.855 Da

References

Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ: A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8921-6. Epub 2002 Jun 17. [12070353 ]
Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ: Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med. 2004 Sep 6;200(5):689-95. Epub 2004 Aug 30. [15337792 ]

Target Details

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

General Function:: Metal ion binding
Specific Function:: Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.
Gene Name:: PDE4B
Uniprot ID:: Q07343
Molecular Weight:: 83342.695 Da

References

Lipworth BJ: Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet. 2005 Jan 8-14;365(9454):167-75. [15639300 ]

Target Details

6. cGMP-specific 3',5'-cyclic phosphodiesterase

General Function:: Metal ion binding
Specific Function:: Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP (PubMed:9714779, PubMed:15489334). Specifically regulates nitric-oxide-generated cGMP (PubMed:15489334).
Gene Name:: PDE5A
Uniprot ID:: O76074
Molecular Weight:: 99984.14 Da

References

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]

Target Details

7. Transcription factor E2F1

General Function:: Transcription factor binding
Specific Function:: Transcription activator that binds DNA cooperatively with DP proteins through the E2 recognition site, 5'-TTTC[CG]CGC-3' found in the promoter region of a number of genes whose products are involved in cell cycle regulation or in DNA replication. The DRTF1/E2F complex functions in the control of cell-cycle progression from G1 to S phase. E2F1 binds preferentially RB1 in a cell-cycle dependent manner. It can mediate both cell proliferation and TP53/p53-dependent apoptosis. Blocks adipocyte differentiation by binding to specific promoters repressing CEBPA binding to its target gene promoters (PubMed:20176812).
Gene Name:: E2F1
Uniprot ID:: Q01094
Molecular Weight:: 46919.28 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	0.715 uM	ATG_E2F_CIS	Attagene

References

Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

Target Details

8. Adenosine receptor A2a

General Function:: Identical protein binding
Specific Function:: Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Gene Name:: ADORA2A
Uniprot ID:: P29274
Molecular Weight:: 44706.925 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	4.37 uM	NVS_GPCR_hAdoRA2a	Novascreen

References

Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

Target Details

9. Adenosine receptor A1

General Function:: Purine nucleoside binding
Specific Function:: Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name:: ADORA1
Uniprot ID:: P30542
Molecular Weight:: 36511.325 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	8.43 uM	NVS_GPCR_hAdoRA1	Novascreen

References

Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

Theophylline (T3D4780)

Structure for T3D4780: Theophylline

Targets

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Binding/Activity Constants

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Binding/Activity Constants

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Binding/Activity Constants

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