Identification
- Generic Name
- Tofisopam
- DrugBank Accession Number
- DB08811
- Background
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.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Anxiety •••••••••••• •••••• Treatment of Depression •••••••••••• •••••• Treatment of Fatigue •••••••••••• •••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- 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
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- 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.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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 Integrate drug-drug
interactions in your software1,2-Benzodiazepine The risk or severity of CNS depression can be increased when Tofisopam is combined with 1,2-Benzodiazepine. Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Tofisopam. Acetazolamide The risk or severity of CNS depression can be increased when Acetazolamide is combined with Tofisopam. Acetophenazine The risk or severity of CNS depression can be increased when Acetophenazine is combined with Tofisopam. Agomelatine The risk or severity of CNS depression can be increased when Agomelatine is combined with Tofisopam. - Food Interactions
- Not Available
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- 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
- Affected organisms
- Humans and other mammals
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. [Article]
- External Links
- Human Metabolome Database
- HMDB0015699
- KEGG Drug
- D01254
- PubChem Compound
- 5502
- PubChem Substance
- 175427099
- ChemSpider
- 5301
- 38365
- ChEBI
- 32241
- ChEMBL
- CHEMBL404216
- PharmGKB
- PA165958428
- PDBe Ligand
- JPU
- Wikipedia
- Tofisopam
- PDB Entries
- 5sii
- MSDS
- Download (398 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 2 Unknown Status Treatment Gout / Hyperuricemia 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- 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 splash10-014i-0039000000-5cb577edbbc8cc8d6873 Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-001i-0009000000-5248ec1cfd970e300010 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-0009000000-eda542c06805b888a0a9 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-000x-1009000000-b66516772ee4e3fa9359 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-001i-0009000000-a5c3a5b2d8dabd2ec772 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0gcc-0029000000-afe89a813677f33c589d Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0006-0169000000-575bed77e0b2a686481c Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 214.1611485 predictedDarkChem Lite v0.1.0 [M-H]- 189.97743 predictedDeepCCS 1.0 (2019) [M+H]+ 213.2100485 predictedDarkChem Lite v0.1.0 [M+H]+ 192.33543 predictedDeepCCS 1.0 (2019) [M+Na]+ 213.6416485 predictedDarkChem Lite v0.1.0 [M+Na]+ 199.2542 predictedDeepCCS 1.0 (2019)
Targets
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- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
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. [Article]
Drug created at January 20, 2011 18:26 / Updated at February 21, 2021 18:52