Antipsychotics are a class of medication for managing psychosis, principally in schizophreniabut also in a range of other psychotic disorders. First-generation antipsychotics are dopamine receptor antagonists and are known as typical antipsychotics. Second-generation antipsychotics are serotonin-dopamine antagonists and are also known as atypical antipsychotics. In this work, researchers describe the discovery of SEP-363856. SEP-363856 is a psychotropic agent with a unique mechanism of action. Especially, SEP-363856 does not exert its antipsychotic-like effects through direct interaction with D2 receptors.

SEP-363856 demonstrates broad efficacy in putative rodent models relating to aspects of schizophrenia, including phencyclidine-induced hyperactivity, prepulse inhibition, and phencyclidine-induced deficits in social interaction. Moreover, SEP-363856 represents a promising candidate for the treatment of schizophrenia and potentially other neuropsychiatric disorders.SEP-363856 exhibits antipsychotic-like efficacy in vivo and demonstrates the potential for treating the positive and negative symptoms of schizophrenia. Furthermore, SEP-363856 may have broad therapeutic efficacy in schizophrenia and potentially other psychiatric disorders.

SEP-363856 (0.3 mg/kg) acts as an anxiolytic but shows a dose-dependent increase in an antipsychotic classification. In addition, SEP-363856 shows a modest antidepressant-like signal. SEP-363856 exhibits high brain penetrance and good systemic bioavailability following oral administration. SEP-363856 penetrates mouse and rat brains after oral administration (10 mg/kg). In addition, SEP-363856 plasma and brain levels are still detectable at 8 hours post-dose with fairly consistent brain/plasma ratios over time. Single oral administration of SEP-363856 in C57BL/6J mice results in a dose-dependent increase in prepulse inhibition compared with the respective vehicle treatment.

All in all, SEP-363856 is CNS active and exhibits a behavioral signature similar to known antipsychotic drugs. SEP-363856 demonstrates antipsychotic- and antidepressant-like activity without inducing catalepsy.

Nina Dedic, et al. SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action. J Pharmacol Exp Ther. 2019 Oct;371(1):1-14.