Compound PZ-1262, a 4-isoquinoline-sulfonamide analog of Brexpiprazole, produces potential antidepressant, anxiolytic and procognitive effects in rodent models.

Background: Novel antipsychotics are characterized by multitarget profile of action, affecting among others, dopamine and serotonin receptors. In a series of experiments, we designed, synthesized and examined two new isoquinoline-sulfonamide analogs of the modern multitarget antipsychotics aripiprazole and brexpiprazole, compounds PZ-1262 and PZ-1264. We hypothesized that the 4-isoquinolinesulfonamide moiety, derived from the structure of 5-HT₆ receptor antagonists, would provide compounds with enhanced activity at 5-HT₆ receptors, along with partial agonistic activity at 5-HT_1A and D₂ receptors.

Methods: The receptor binding profile, functional activity, and metabolic stability of PZ-1262 and PZ-1264 were evaluated through in vitro assays. Potential antipsychotic, antidepressant, anxiolytic, and pro-cognitive effects were assessed using in vivo behavioral tests in rodents.

Results: In vitro, PZ compounds demonstrated partial agonistic activity at 5-HT_1A receptor, antagonistic activity at D₂ and D₃ as well as 5-HT_2A, 5-HT₆ and 5-HT₇ receptors and metabolic stability. In vivo, both compounds enhanced phencyclidine-induced hyperactivity in rats and decreased immobility time in the forced swim test in mice, without influencing spontaneous locomotor activity. In the novel object recognition test in rats, they demonstrated pro-cognitive effects in phencyclidine disturbed conditions. PZ-1262 potentiated D-amphetamine-induced hyperactivity, exhibited anxiolytic-like effects in the four plates test in mice, and demonstrated significant brain penetration.

Conclusions: The complex pharmacodynamic profile translated into the useful psychotropic effects. While the compounds potentiated D-amphetamine- and phencyclidine-induced hyperactivity, this action could be regarded as a desired activating effect rather than evidence against antipsychotic-like efficacy. Present findings point to PZ-1262 as a more promising lead compound for further research.