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N. DEDIC1, P. G. JONES1, S. C. HOPKINS1, R. LEW1, T. HANANIA2, U. C. CAMPBELL1, K. S. KOBLAN1


1Sunovion Pharmaceuticals Inc., Marlborough, MA; 2Psychogenics Inc., Paramus, NJ.


For the past 50 years, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D2 receptors. Drug development of non-D2 compounds, seeking to avoid the limiting side effects of dopamine blockade, has failed to date to yield new medicines for patients. Here 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 known as SmartCube®, in combination with in vitro screening, aimed at developing non-D2 (anti-target) compounds that could nevertheless retain efficacy across a variety of D2-based animal models of schizophrenia. SEP-856 demonstrated broad efficacy in rodent models relating to positive- and negative symptoms of schizophrenia, including Phencyclidine (PCP)-induced hyperactivity, prepulse inhibition and PCP-induced deficits in social interaction. Autoradiography and positron emission tomography studies in rats and non-human primates demonstrated lack of D2 receptor occupancy by SEP-856 at concentrations up to 200-fold greater than those observed to be behaviorally efficacious. In addition to its favorable pharmacokinetic properties and the absence of catalepsy, SEP-856’s broad profile was further highlighted by its antidepressant activity in the mouse forced swim test and robust suppression of rapid eye movement sleep in the rat. Although, the mechanism of action has not been fully elucidated, in vitro and in vivo pharmacology data suggest that agonism at both 5-HT1A receptors and trace amine-associated receptor 1 (TAAR1) are integral to its efficacy. This was further corroborated with electrophysiological slice recordings, demonstrating inhibition of dorsal raphe nucleus and ventral tegmental area neuronal firing via 5-HT1A and TAAR1 receptors, respectively. Based on its unique mechanism of action and broad efficacy in preclinical animals models, SEP-856 was advanced into clinical development and represents a promising candidate for the treatment of schizophrenia and potentially other neuropsychiatric disorders.