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

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 γ-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 μM) followed by PDE-10A1 (0.92 μM), PDE-3 (1.98 μM) and PDE-2A3 (2.11 μM). 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.

Protective effects of phosphodiesterase 2 inhibitor on depression- and anxiety-like behaviors: Involvement of antioxidant and anti-apoptotic mechanisms

“…Inhibition of PDEs can increase intracellular cAMP and/or cGMP and affect the downstream signaling [12,13]. Some PDE inhibitors, such as those of PDE4 and PDE5, have been known for their neuroprotective effects against emotion and cognitive disorders, but are also known for their side effects [10,14]. PDE2, as a relatively new player in this field, catalyzes both cGMP and cAMP and is found in brain regions such as hippocampus and amygdala that are essential components of the neural circuitry mediating psychiatric disorders [15].…”

The emergence of new psychoactive substance (NPS) benzodiazepines: A review

“…brotizolam) have a triazole ring fused to the diazepine ring, much like the triazolobenzodiazepines. 2,3‐benzodiazepines such as tofisopam exist (Figure H) but despite them having the benzodiazepine ring structure they exhibit different pharmacological properties compared with the other benzodiazepines; they act via the 2‐amino‐3‐(3‐hydroxy‐5‐methylisoxazol‐4‐yl)propionic acid (AMPA) glutamate receptor but still exhibit anxiolytic activity . To the best of the authors' knowledge there are no reports of abuse of 2,3‐benzodiazepines.…”

Tofisopam: Prospects for Non-Hormonal Therapy of Neuro-Vegetative and Psycho-Emotional Disorders Associated With Menopausal Syndrome

“…Хотя у тофизопама и классических 1,4-бензодиазепинов общая химическая основа. В экспериментах на животных установлено, что тофизопам не связывается в ЦНС ни с 1-4 бензодиазепиновыми, ни с ГАМК-рецеп торами (ГАМК -γ-аминомасляная кислота), но потен цирует связывание других бензодиазепинов с бензодиазепиновыми рецепторами [9,10]. Показано, что места связывания тофизопама локализованы исключительно на базальных ганглиях.…”

“…Если препараты использовать постоянно, повторения такого эпизода можно замедлить или даже предотвратить. Однако лечение классическими антипсихотическими препаратами затрудняется вследствие побочных эффектов: негативное воздействие на внимание, концентрацию, познание и память [9].…”