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Identification
NameTofisopam
Accession NumberDB08811
TypeSmall Molecule
GroupsApproved
Description

Tofisopam (marketed under brand names Emandaxin and Grandaxin) is a 2,3-benzodiazepine drug which is a benzodiazepine derivative. In contrast to classical 1,4-benzodiazepines, the compound does not bind to the benzodiazepine binding site of the gamma-aminobutyric acid receptor and its psychopharmacological profile differs from such compounds. Although Tofisopam is not approved for sale in North America, it is approved for use in various countries worldwide, including parts of Europe. The D-enantiomer (dextofisopam) is currently in phase II trials in the U.S. for the treatment of irritable bowel syndrome.

Structure
Thumb
Synonyms
Emandaxin
Tofizopam
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
EmandaxinNot Available
GrandaxinNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIUZC80HAU42
CAS number22345-47-7
WeightAverage: 382.4528
Monoisotopic: 382.18925733
Chemical FormulaC22H26N2O4
InChI KeyInChIKey=RUJBDQSFYCKFAA-UHFFFAOYSA-N
InChI
InChI=1S/C22H26N2O4/c1-7-15-13(2)23-24-22(14-8-9-18(25-3)19(10-14)26-4)17-12-21(28-6)20(27-5)11-16(15)17/h8-12,15H,7H2,1-6H3
IUPAC Name
1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine
SMILES
CCC1C2=CC(OC)=C(OC)C=C2C(=NN=C1C)C1=CC(OC)=C(OC)C=C1
Taxonomy
ClassificationNot classified
Pharmacology
IndicationFor the treatment of anxiety and alcohol withdrawal.
PharmacodynamicsLike other benzodiazepines, tofisopam possesses anxiolytic properties but unlike other benzodiazepines it does not have anticonvulsant, sedative, skeletal muscle relaxant, motor skill-impairing or amnestic properties. While it may not be an anticonvulsant in and of itself, it has been shown to enhance the anticonvulsant action of classical 1,4-benzodiazepines such as diazepam (but not sodium valproate, carbamazepine, phenobarbital, or phenytoin).
Mechanism of actionTofisopam does not bind to the benzodiazepine binding site of the gamma-aminobutyric acid receptor. One study (Rundfeldt C. et al.) has shown that tofisopam acts as an isoenzyme-selective inhibitor of phosphodiesterases (PDEs) with highest affinity to PDE-4A1 (0.42 μM) followed by PDE-10A1 (0.92 μM), PDE-3 (1.98 μM) and PDE-2A3 (2.11 μM).
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic.

Route of eliminationNot Available
Half life6-8 hours
ClearanceNot Available
ToxicityThe onset of impairment of consciousness is relatively rapid in benzodiazepine poisoning. Onset is more rapid following larger doses and with agents of shorter duration of action. The most common and initial symptom is somnolence. This may progress to coma (Grade I or Grade II) following very large ingestions. Oral, rat LD50 is 825 mg/kg.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9382
Caco-2 permeable+0.6064
P-glycoprotein substrateSubstrate0.6263
P-glycoprotein inhibitor IInhibitor0.7778
P-glycoprotein inhibitor IINon-inhibitor0.6118
Renal organic cation transporterNon-inhibitor0.7738
CYP450 2C9 substrateNon-substrate0.8036
CYP450 2D6 substrateNon-substrate0.7068
CYP450 3A4 substrateSubstrate0.6068
CYP450 1A2 substrateInhibitor0.5176
CYP450 2C9 inhibitorNon-inhibitor0.5583
CYP450 2D6 inhibitorNon-inhibitor0.8642
CYP450 2C19 inhibitorInhibitor0.5909
CYP450 3A4 inhibitorInhibitor0.6101
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7118
Ames testNon AMES toxic0.6138
CarcinogenicityNon-carcinogens0.7679
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6346 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.989
hERG inhibition (predictor II)Non-inhibitor0.8089
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point156.5 °CPhysProp
Predicted Properties
PropertyValueSource
Water Solubility0.00239 mg/mLALOGPS
logP4.29ALOGPS
logP3.83ChemAxon
logS-5.2ALOGPS
pKa (Strongest Basic)-2.2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area61.64 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity109.03 m3·mol-1ChemAxon
Polarizability42.14 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis ReferenceNot Available
General References
  1. Rundfeldt C, Socala K, Wlaz P: The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis. J Neural Transm (Vienna). 2010 Nov;117(11):1319-25. doi: 10.1007/s00702-010-0507-3. Epub 2010 Oct 22. [PubMed:20967473 ]
External Links
ATC CodesN05BA23
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (398 KB)
Interactions
Drug Interactions
Drug
AminophyllineThe therapeutic efficacy of Tofisopam can be decreased when used in combination with Aminophylline.
ClozapineThe risk or severity of adverse effects can be increased when Tofisopam is combined with Clozapine.
DyphyllineThe therapeutic efficacy of Tofisopam can be decreased when used in combination with Dyphylline.
FosphenytoinThe serum concentration of Fosphenytoin can be increased when it is combined with Tofisopam.
Gamma Hydroxybutyric AcidTofisopam may increase the central nervous system depressant (CNS depressant) activities of Gamma Hydroxybutyric Acid.
MethadoneTofisopam may increase the central nervous system depressant (CNS depressant) activities of Methadone.
OlanzapineThe risk or severity of adverse effects can be increased when Olanzapine is combined with Tofisopam.
PhenytoinThe serum concentration of Phenytoin can be increased when it is combined with Tofisopam.
Sodium oxybateTofisopam may increase the central nervous system depressant (CNS depressant) activities of Sodium oxybate.
TeduglutideThe serum concentration of Tofisopam can be increased when it is combined with Teduglutide.
TheophyllineThe therapeutic efficacy of Tofisopam can be decreased when used in combination with Theophylline.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
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
  1. Rundfeldt C, Socala K, Wlaz P: The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis. J Neural Transm (Vienna). 2010 Nov;117(11):1319-25. doi: 10.1007/s00702-010-0507-3. Epub 2010 Oct 22. [PubMed:20967473 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Metal ion binding
Specific Function:
Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.
Gene Name:
PDE10A
Uniprot ID:
Q9Y233
Molecular Weight:
88411.71 Da
References
  1. Rundfeldt C, Socala K, Wlaz P: The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis. J Neural Transm (Vienna). 2010 Nov;117(11):1319-25. doi: 10.1007/s00702-010-0507-3. Epub 2010 Oct 22. [PubMed:20967473 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
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
  1. Rundfeldt C, Socala K, Wlaz P: The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis. J Neural Transm (Vienna). 2010 Nov;117(11):1319-25. doi: 10.1007/s00702-010-0507-3. Epub 2010 Oct 22. [PubMed:20967473 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Tpr domain 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.Isoform PDE2A2: Regulates Mitochondrial cAMP Levels and Respiration.
Gene Name:
PDE2A
Uniprot ID:
O00408
Molecular Weight:
105715.85 Da
References
  1. Rundfeldt C, Socala K, Wlaz P: The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis. J Neural Transm (Vienna). 2010 Nov;117(11):1319-25. doi: 10.1007/s00702-010-0507-3. Epub 2010 Oct 22. [PubMed:20967473 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Toth M, Bajnogel J, Egyed A, Drabant S, Tomlo J, Klebovich I: [Effect of tofisopam on CYP3A4 enzyme activity on human recombinant 3A4 supersome]. Acta Pharm Hung. 2005;75(4):195-8. [PubMed:16711396 ]
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Drug created on January 20, 2011 11:26 / Updated on August 17, 2016 12:24