Tofisopam

Synonyms :
Emandaxin, Tofizopam

Status : approved

Category

Antidepressive Agents

Therapeutic Classification

ANXIOLYTICS

NERVOUS SYSTEM
PSYCHOLEPTICS
ANXIOLYTICS
Benzodiazepines

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.

Used

For the treatment of anxiety and alcohol withdrawal.

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).

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).

Toxic Effect

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.

Metabolism

Hepatic.

Half Life

6-8 hours

Chemical Classification

Chemical Name

Emandaxin

Drug Drug Interactions

  •  Aminophylline  : Theophylline Derivatives may diminish the therapeutic effect of Benzodiazepines.
  •  Clozapine  : May enhance the adverse/toxic effect of Clozapine.
  •  Dyphylline  : Theophylline Derivatives may diminish the therapeutic effect of Benzodiazepines.
  •  Fosphenytoin  : May increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy.
  •  Gamma Hydroxybutyric Acid  : May enhance the CNS depressant effect of Sodium Oxybate.
  •  Methadone  : May enhance the CNS depressant effect of Methadone.
  •  Olanzapine  : Olanzapine may enhance the adverse/toxic effect of Benzodiazepines.
  •  Phenytoin  : May increase the serum concentration of Phenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy.
  •  Sodium oxybate  : May enhance the CNS depressant effect of Sodium oxybate.
  •  Teduglutide  : Teduglutide may increase the serum concentration of Benzodiazepines.
  •  Theophylline  : Theophylline Derivatives may diminish the therapeutic effect of Benzodiazepines.

Calculated Property

kind Value Source
logP 4.29 ALOGPS
logS -5.2 ALOGPS
Water Solubility 2.39e-03 g/l ALOGPS
logP 3.83 ChemAxon
IUPAC Name 1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine ChemAxon
Traditional IUPAC Name seriel ChemAxon
Molecular Weight 382.4528 ChemAxon
Monoisotopic Weight 382.18925733 ChemAxon
SMILES CCC1C2=CC(OC)=C(OC)C=C2C(=NN=C1C)C1=CC(OC)=C(OC)C=C1 ChemAxon
Molecular Formula C22H26N2O4 ChemAxon
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 ChemAxon
InChIKey InChIKey=RUJBDQSFYCKFAA-UHFFFAOYSA-N ChemAxon
Polar Surface Area (PSA) 61.64 ChemAxon
Refractivity 109.03 ChemAxon
Polarizability 42.14 ChemAxon
Rotatable Bond Count 6 ChemAxon
H Bond Acceptor Count 6 ChemAxon
H Bond Donor Count 0 ChemAxon
pKa (strongest basic) -2.2 ChemAxon
Physiological Charge 0 ChemAxon
Number of Rings 3 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 1 ChemAxon
Ghose Filter 1 ChemAxon
MDDR-Like Rule 1 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • cAMP-specific 3′,5′-cyclic phosphodiesterase 4A : in Human
  • cAMP and cAMP-inhibited cGMP 3′,5′-cyclic phosphodiesterase 10A : in Human
  • cGMP-inhibited 3′,5′-cyclic phosphodiesterase A : in Human
  • cGMP-dependent 3′,5′-cyclic phosphodiesterase : in Human