Identification

Name
Tofisopam
Accession Number
DB08811
Type
Small Molecule
Groups
Experimental
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
International/Other Brands
Emandaxin / Grandaxin
Categories
UNII
UZC80HAU42
CAS number
22345-47-7
Weight
Average: 382.4528
Monoisotopic: 382.18925733
Chemical Formula
C22H26N2O4
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

Pharmacology

Indication

For the treatment of anxiety and alcohol withdrawal.

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. 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 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
Human
UcAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
inhibitor
Human
UcGMP-inhibited 3',5'-cyclic phosphodiesterase A
inhibitor
Human
UcGMP-dependent 3',5'-cyclic phosphodiesterase
inhibitor
Human
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
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
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Tofisopam.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Tofisopam.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Tofisopam is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineThe therapeutic efficacy of Tofisopam can be decreased when used in combination with 3-isobutyl-1-methyl-7H-xanthine.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Tofisopam.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Tofisopam.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Tofisopam.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Tofisopam.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Tofisopam.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Tofisopam.
Food Interactions
Not Available

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. [PubMed:20967473]
External Links
Human Metabolome Database
HMDB0015699
KEGG Drug
D01254
PubChem Compound
5502
PubChem Substance
175427099
ChemSpider
5301
ChEBI
32241
ChEMBL
CHEMBL404216
PharmGKB
PA165958428
Wikipedia
Tofisopam
ATC Codes
N05BA23 — Tofisopam
MSDS
Download (398 KB)

Clinical Trials

Clinical Trials
Not Available

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-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Benzodiazepine / Dimethoxybenzene / O-dimethoxybenzene / Phenoxy compound / Anisole / Phenol ether / Methoxybenzene / Alkyl aryl ether / Monocyclic benzene moiety / Benzenoid
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not 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
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. [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 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. [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
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. [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 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. [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 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. [PubMed:16711396]

Drug created on January 20, 2011 11:26 / Updated on November 02, 2018 06:54