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For the past 50 years, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D 2 receptors. Drug development of non-D 2 compounds, seeking to avoid the limiting side effects of dopamine receptor blockade, has failed to date to yield new medicines for patients. In this work, we report the discovery of SEP-363856 (SEP-856), a novel psychotropic agent with a unique mechanism of action. SEP-856 was discovered in a medicinal chemistry effort utilizing a high throughput, high content, mouse-behavior phenotyping platform, in combination with in vitro screening, aimed at developing non-D 2 (anti-target) compounds that could nevertheless retain efficacy across multiple animal models sensitive to D 2 -based pharmacological mechanisms. SEP-856 demonstrated broad efficacy in putative rodent models relating to aspects of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition, and PCP-induced deficits in social interaction. In addition to its favorable pharmacokinetic properties, lack of D 2 receptor occupancy, and the absence of catalepsy, SEP-856's broad profile was further highlighted by its robust suppression of rapid eye movement sleep in rats. Although the mechanism of action has not been fully elucidated, in vitro and in vivo pharmacology data as well as slice and in vivo electrophysiology recordings suggest that agonism at both trace amine-associated receptor 1 and 5-HT 1A receptors is integral to its efficacy. Based on the preclinical data and its unique mechanism of action, SEP-856 is a promising new agent for the treatment of schizophrenia and represents a new pharmacological class expected to lack the side effects stemming from blockade of D 2 signaling. SIGNIFICANCE STATEMENT: Since the discovery of chlorpromazine in the 1950s, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D 2 receptors, which is associated with substantial side effects and little to no efficacy in treating the negative and cognitive symptoms of schizophrenia. In this study, we describe the discovery and pharmacology of SEP-363856, a novel psychotropic agent that does not exert its antipsychotic-like effects through direct interaction with D 2 receptors. Although the mechanism of action has not been fully elucidated, our data suggest that agonism at both trace amine-associated receptor 1 and 5-HT 1A receptors is integral to its efficacy. Based on its unique profile in preclinical species, SEP-363856 represents a promising candidate for the treatment of schizophrenia and potentially other neuropsychiatric disorders.

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂ Receptor Mechanism of Action