Tofisopam

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
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.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofAnxiety••••••••••••••••••
Treatment ofDepression••••••••••••••••••
Treatment ofFatigue••••••••••••••••••
Contraindications & Blackbox Warnings
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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).

TargetActionsOrganism
UcAMP-specific 3',5'-cyclic phosphodiesterase 4A
inhibitor
Humans
UcAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
inhibitor
Humans
UcGMP-inhibited 3',5'-cyclic phosphodiesterase A
inhibitor
Humans
UcGMP-dependent 3',5'-cyclic phosphodiesterase
inhibitor
Humans
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
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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
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.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of CNS depression can be increased when Tofisopam is combined with 1,2-Benzodiazepine.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Tofisopam.
AcetazolamideThe risk or severity of CNS depression can be increased when Acetazolamide is combined with Tofisopam.
AcetophenazineThe risk or severity of CNS depression can be increased when Acetophenazine is combined with Tofisopam.
AgomelatineThe risk or severity of CNS depression can be increased when Agomelatine is combined with Tofisopam.
Food Interactions
Not Available

Products

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International/Other Brands
Emandaxin / Grandaxin

Categories

ATC Codes
N05BA23 — Tofisopam
Drug Categories
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
  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. [Article]
Human Metabolome Database
HMDB0015699
KEGG Drug
D01254
PubChem Compound
5502
PubChem Substance
175427099
ChemSpider
5301
RxNav
38365
ChEBI
32241
ChEMBL
CHEMBL404216
PharmGKB
PA165958428
PDBe Ligand
JPU
Wikipedia
Tofisopam
PDB Entries
5sii
MSDS
Download (398 KB)

Clinical Trials

Clinical Trials
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PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
2Unknown StatusTreatmentGout Flares / Hyperuricemia1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)156.5 °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 RuleNoChemaxon
MDDR-like RuleYesChemaxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-014i-0039000000-5cb577edbbc8cc8d6873
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-0009000000-5248ec1cfd970e300010
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-0009000000-eda542c06805b888a0a9
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-000x-1009000000-b66516772ee4e3fa9359
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-0009000000-a5c3a5b2d8dabd2ec772
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0gcc-0029000000-afe89a813677f33c589d
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-0169000000-575bed77e0b2a686481c
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-214.1611485
predicted
DarkChem Lite v0.1.0
[M-H]-189.97743
predicted
DeepCCS 1.0 (2019)
[M+H]+213.2100485
predicted
DarkChem Lite v0.1.0
[M+H]+192.33543
predicted
DeepCCS 1.0 (2019)
[M+Na]+213.6416485
predicted
DarkChem Lite v0.1.0
[M+Na]+199.2542
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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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
  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. [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
  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. [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
  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. [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
  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. [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
  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. [Article]

Drug created at January 20, 2011 18:26 / Updated at February 21, 2021 18:52