The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis.

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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 ID

20967473 [ View in PubMed

]

Abstract

Tofisopam is a member of the 2,3-benzodiazepine compound family which is marketed for the treatment of anxiety in some European countries. 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. In addition to anxiolytic properties, antipsychotic effects are reported. We now show that tofisopam, 50 mg/kg intraperitoneally (i.p.), administered in parallel to repeated doses of dizocilpine 0.2 mg/kg i.p. can ameliorate dizocilpine-induced prolongation of immobility, which is considered to be a model of negative symptoms of psychosis. We further show that tofisopam acts as an isoenzyme-selective inhibitor of phosphodiesterases (PDEs) with highest affinity to PDE-4A1 (0.42 muM) followed by PDE-10A1 (0.92 muM), PDE-3 (1.98 muM) and PDE-2A3 (2.11 muM). The data indicate that tofisopam is an interesting candidate for the adjuvant treatment of psychosis with focus on negative symptoms. Combined partial inhibition of PDE-4 and PDE-10 as well as PDE-2 may be the underlying mechanism to this activity. Due to the good safety profile of tofisopam as evident from long-term use of this agent in patients, it may be concluded that dual or triple inhibition of PDE isoenzymes with additive or synergistic effects may be an interesting approach to pharmacological activity, resulting in active compounds with beneficial safety profile. Dose-limiting side effects such as emesis induced by selective inhibition of PDE-4 may be prevented by such strategies.

DrugBank Data that Cites this Article

Drugs

Tofisopam

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Tofisopam	cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A	Protein	Humans	Unknown	Inhibitor	Details
Tofisopam	cAMP-specific 3',5'-cyclic phosphodiesterase 4A	Protein	Humans	Unknown	Inhibitor	Details
Tofisopam	cGMP-dependent 3',5'-cyclic phosphodiesterase	Protein	Humans	Unknown	Inhibitor	Details
Tofisopam	cGMP-inhibited 3',5'-cyclic phosphodiesterase A	Protein	Humans	Unknown	Inhibitor	Details