Tofisopam
Identification
- Name
- Tofisopam
- Accession Number
- DB08811
- 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.
- Type
- Small Molecule
- Groups
- Experimental
- Structure
Structure for Tofisopam (DB08811)
- Weight
- Average: 382.4528
Monoisotopic: 382.18925733 - Chemical Formula
- C22H26N2O4
- Synonyms
- Tofisopam
- Tofisopamum
- External IDs
- Egyt 341
Pharmacology
- Indication
For the treatment of anxiety and alcohol withdrawal.
- Associated Conditions
- Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
Learn More- Pharmacodynamics
Like 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. It enhances the anticonvulsant activity of 1,4-benzodiazepines like diazepam but not sodium valproate, carbamazepine, phenobarbital, or phenytoin.
- Mechanism of action
Tofisopam 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).
Target Actions Organism UcAMP-specific 3',5'-cyclic phosphodiesterase 4A inhibitorHumans UcAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A inhibitorHumans UcGMP-inhibited 3',5'-cyclic phosphodiesterase A inhibitorHumans UcGMP-dependent 3',5'-cyclic phosphodiesterase inhibitorHumans - Absorption
- Not Available
- Volume of distribution
- Not Available
- Protein binding
- Not Available
- Metabolism
Hepatic.
- Route of elimination
- Not Available
- Half-life
6-8 hours
- Clearance
- Not Available
- Adverse Effects
Learn about our commercial Adverse Effects data.
Learn More- Toxicity
The 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
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Unlock Additional DataAcenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Tofisopam. Acetazolamide The risk or severity of adverse effects can be increased when Acetazolamide is combined with Tofisopam. Acetophenazine The risk or severity of adverse effects can be increased when Acetophenazine is combined with Tofisopam. Aclidinium Tofisopam may increase the central nervous system depressant (CNS depressant) activities of Aclidinium. Agomelatine The risk or severity of adverse effects can be increased when Agomelatine is combined with Tofisopam. Alfentanil The risk or severity of adverse effects can be increased when Alfentanil is combined with Tofisopam. Alfuzosin The metabolism of Alfuzosin can be decreased when combined with Tofisopam. Alimemazine The risk or severity of adverse effects can be increased when Alimemazine is combined with Tofisopam. Almotriptan The risk or severity of adverse effects can be increased when Almotriptan is combined with Tofisopam. Alosetron The risk or severity of adverse effects can be increased when Alosetron is combined with Tofisopam. Additional Data Available- Extended DescriptionExtended DescriptionAvailable for Purchase
Extended description of the mechanism of action and particular properties of each drug interaction.
Learn more - SeveritySeverityAvailable for Purchase
A severity rating for each drug interaction, from minor to major.
Learn more - Evidence LevelEvidence LevelAvailable for Purchase
A rating for the strength of the evidence supporting each drug interaction.
Learn more - ActionActionAvailable for Purchase
An effect category for each drug interaction. Know how this interaction affects the subject drug.
Learn more
- Food Interactions
- Not Available
Products
- International/Other Brands
- Emandaxin / Grandaxin
Categories
- ATC Codes
- N05BA23 — Tofisopam
- Drug Categories
- Anti-Anxiety Agents
- Antidepressive Agents
- Benzazepines
- Benzodiazepines and benzodiazepine derivatives
- Central Nervous System Agents
- Central Nervous System Depressants
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
- Cytochrome P-450 Enzyme Inhibitors
- Heterocyclic Compounds, Fused-Ring
- Nervous System
- Psycholeptics
- Psychotropic Drugs
- Stereoisomerism
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as benzodiazepines. These are organic compounds containing a benzene ring fused to either isomers of diazepine(unsaturated seven-member heterocycle with two nitrogen atoms replacing two carbon atoms).
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Benzodiazepines
- Sub Class
- Not Available
- Direct Parent
- Benzodiazepines
- Alternative Parents
- Dimethoxybenzenes / Phenoxy compounds / Anisoles / Alkyl aryl ethers / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Hydrocarbon derivatives
- Substituents
- Alkyl aryl ether / Anisole / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Benzodiazepine / Dimethoxybenzene / Ether / Hydrocarbon derivative / Methoxybenzene
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
Chemical Identifiers
- UNII
- UZC80HAU42
- CAS number
- 22345-47-7
- InChI Key
- 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
References
- General References
- 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
- Human Metabolome Database
- HMDB0015699
- KEGG Drug
- D01254
- PubChem Compound
- 5502
- PubChem Substance
- 175427099
- ChemSpider
- 5301
- 38365
- ChEBI
- 32241
- ChEMBL
- CHEMBL404216
- PharmGKB
- PA165958428
- Wikipedia
- Tofisopam
- MSDS
- Download (398 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 2 Unknown Status Treatment Gouty Arthritis / Hyperuricemia 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 50 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 156.5 °C PhysProp - Predicted Properties
Property Value Source Water Solubility 0.00239 mg/mL ALOGPS logP 4.29 ALOGPS logP 3.83 ChemAxon logS -5.2 ALOGPS pKa (Strongest Basic) -2.2 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 6 ChemAxon Hydrogen Donor Count 0 ChemAxon Polar Surface Area 61.64 Å2 ChemAxon Rotatable Bond Count 6 ChemAxon Refractivity 109.03 m3·mol-1 ChemAxon Polarizability 42.14 Å3 ChemAxon Number of Rings 3 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule No ChemAxon MDDR-like Rule Yes ChemAxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.9382 Caco-2 permeable + 0.6064 P-glycoprotein substrate Substrate 0.6263 P-glycoprotein inhibitor I Inhibitor 0.7778 P-glycoprotein inhibitor II Non-inhibitor 0.6118 Renal organic cation transporter Non-inhibitor 0.7738 CYP450 2C9 substrate Non-substrate 0.8036 CYP450 2D6 substrate Non-substrate 0.7068 CYP450 3A4 substrate Substrate 0.6068 CYP450 1A2 substrate Inhibitor 0.5176 CYP450 2C9 inhibitor Non-inhibitor 0.5583 CYP450 2D6 inhibitor Non-inhibitor 0.8642 CYP450 2C19 inhibitor Inhibitor 0.5909 CYP450 3A4 inhibitor Inhibitor 0.6101 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7118 Ames test Non AMES toxic 0.6138 Carcinogenicity Non-carcinogens 0.7679 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 2.6346 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.989 hERG inhibition (predictor II) Non-inhibitor 0.8089
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- 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
- Uniprot Name
- cAMP-specific 3',5'-cyclic phosphodiesterase 4A
- Molecular Weight
- 98142.155 Da
References
- 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
- Humans
- 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 wit...
- Gene Name
- PDE10A
- Uniprot ID
- Q9Y233
- Uniprot Name
- cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
- Molecular Weight
- 88411.71 Da
References
- 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
- Humans
- 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
- Uniprot Name
- cGMP-inhibited 3',5'-cyclic phosphodiesterase A
- Molecular Weight
- 124978.06 Da
References
- 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
- Humans
- 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 Mit...
- Gene Name
- PDE2A
- Uniprot ID
- O00408
- Uniprot Name
- cGMP-dependent 3',5'-cyclic phosphodiesterase
- Molecular Weight
- 105715.85 Da
References
- 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
- Humans
- 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 react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- 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]
Drug created on January 20, 2011 11:26 / Updated on January 06, 2021 20:12