What is the mechanism of action of Tofisopam?

Tofisopam Mechanism of Action

Tofisopam is a 2,3-benzodiazepine that does not bind to classical benzodiazepine or GABA receptors, but instead acts primarily as a selective phosphodiesterase (PDE) inhibitor with mixed dopaminergic properties. 1, 2

Primary Mechanisms

Phosphodiesterase Inhibition

• Tofisopam selectively inhibits multiple PDE isoenzymes with the following affinities: PDE-4A1 (0.42 μM, highest affinity), PDE-10A1 (0.92 μM), PDE-3 (1.98 μM), and PDE-2A3 (2.11 μM). 2
• This combined partial inhibition of PDE-4, PDE-10, and PDE-2 distinguishes it from classical benzodiazepines and may explain its unique clinical profile without typical benzodiazepine side effects. 2
• The dual or triple PDE inhibition strategy appears to provide therapeutic activity while avoiding dose-limiting side effects like emesis that occur with selective PDE-4 inhibition alone. 2

Dopaminergic Effects

• Tofisopam exhibits mixed dopamine agonist and antagonist properties, which is highly atypical for anxiolytic agents. 1, 3
• At doses above 200 mg/kg, tofisopam produces neuroleptic-like effects including catalepsy, ptosis, decreased pentetrazol threshold, and potentiation of amphetamine and apomorphine stereotypy. 1
• Tofisopam acutely increases the sensitivity of central dopaminergic receptors, enhancing the behavioral actions of both direct dopamine agonists (apomorphine) and indirect agonists (amphetamine, amineptine). 4
• This dopaminergic receptor sensitization can be prevented by chronic lithium pretreatment. 4

Receptor Binding Profile

What Tofisopam Does NOT Do

• Tofisopam does not bind to classical 1,4-benzodiazepine receptors or GABA receptors in the CNS, which explains why it lacks the sedative, anticonvulsant, and muscle relaxant effects characteristic of traditional benzodiazepines. 1, 3
• This structural difference (nitrogen atoms at positions 2,3 rather than 1,4) is responsible for its distinct pharmacological profile. 1

Indirect GABAergic Modulation

• Although tofisopam does not directly bind to benzodiazepine or GABA receptors, it enhances the binding of classical benzodiazepines and muscimol (a GABA agonist) to their respective binding sites. 1
• This indirect modulation may contribute to its anxiolytic effects through a different pathway than classical benzodiazepines. 1

Clinical Pharmacology Distinctions

Unique Behavioral Profile

• Tofisopam produces anxiolytic effects without appreciable sedation, muscle relaxation, or anticonvulsant activity at therapeutic doses. 1, 3
• It does not induce sleep even at subtoxic doses and only enhances barbiturate and ethanol effects at high doses. 1
• No tolerance develops after repeated administration, unlike classical benzodiazepines. 1

Antipsychotic Properties

• Tofisopam at 50 mg/kg can ameliorate dizocilpine-induced prolongation of immobility in animal models, suggesting potential efficacy for negative symptoms of psychosis. 2
• This effect is likely mediated through the combined PDE-4 and PDE-10 inhibition. 2

Drug Interaction Considerations

CYP3A4 Inhibition

• Tofisopam inhibits CYP3A4 enzyme activity in a dose-dependent manner with an IC50 of 0.8 μmol/L in vitro studies. 5
• At concentrations of 0.1 to 5 μmol/L, tofisopam inhibited CYP3A4 activity by 4% to 94%, respectively. 5
• This inhibition is approximately one order of magnitude weaker than ketoconazole (a potent CYP3A4 inhibitor with IC50 of 0.03 μmol/L), but clinically relevant interactions have been reported with immunosuppressive agents that are CYP3A4 substrates. 5
• When prescribing tofisopam with CYP3A4 substrates (cyclosporine, tacrolimus, certain statins), monitor drug levels closely and anticipate the need for dose reduction of the CYP3A4 substrate. 5

Proposed Mechanism for Anxiolytic Activity

Tofisopam likely reduces anxiety by increasing patients' ability to cope with daily tasks rather than through tranquilization, distinguishing it from classical anxiolytics. 3 This coping-enhancement mechanism may result from the combination of PDE inhibition (particularly PDE-4 and PDE-10) and dopaminergic modulation, creating a unique pharmacological profile that provides anxiolysis without sedation or cognitive impairment. 2, 3