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. At the time these studies were conducted, all authors were employees of either Sunovion Pharmaceuticals or PsychoGenics. Some authors are inventors on patents related to the subject matter. 1 N.D. and P.G.J. contributed equally to the work.

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. This observation provided an opportunity to map the determinants of receptor affinity exhibited by BIBN4096BS and the truncated analogs, Compounds 1 and 2. All three compounds exhibited higher affinity for the human receptor, human CRLR/human RAMP1, than for the rat receptor, rat CRLR/rat RAMP1. We have now demonstrated that this species selectivity was directed exclusively by RAMP1. By generating recombinant human/rat CRLR/RAMP1 receptors, we demonstrated that co-expression of human CRLR with rat RAMP1 produced rat receptor pharmacology, and vice versa. Moreover, with rat/human RAMP1 chimeras and site-directed mutants, we have identified a single amino acid at position 74 of RAMP1 that modulates the affinity of small molecule antagonists for CRLR/RAMP1. Replacement of lysine 74 in rat RAMP1 with tryptophan (the homologous amino acid in the human receptor) resulted in a >100-fold increase in antagonist affinities, similar to the K i values for the human receptor. These observations suggest that important determinants of small molecule antagonist affinity for the CGRP receptor reside within the extracellular region of RAMP1 and provide evidence that this receptor accessory protein may participate in antagonist binding.CGRP is a 37-amino acid neuropeptide that is expressed in a variety of cell types in both the central and peripheral nervous systems (5). In many tissues, CGRP-containing fibers are closely associated with blood vessels (6). Among the various physiological functions reported for CGRP, the most pronounced is vasodilation. CGRP is the most powerful of the vasodilator transmitters (7), and its vasoactive effects have been demonstrated in a variety of blood vessels (8), including those in the cerebral, coronary, and mesenteric vasculature.Mounting evidence suggests that CGRP is involved in the pathophysiology of migraine headache (9). Migraine is thought to be associated with dilation of cerebral blood vessels and activation of the trigeminovascular system (10). During the headache phase of a migraine, CGRP levels are elevated in the cranial circulation (11, 12). Successful treatment of the headache with sumatriptan resulted in normalization of CGRP levels (12), thus implicating CGRP in the pathophysiology of this disorder. Moreover, intravenous administration of CGRP to migraineurs induced a delayed migrainous headache in some patients (13). These observations suggest that inhibition of CGRP-mediated vasodilation may have therapeutic utility in the treatment of migraine.Research in the area of CGRP has intensified in recent years due in large part to the identification of its receptor, CRLR 1 (14), and the cloning of the receptor activity-modifying proteins (RAMPs) (1) and receptor component protein (15). CGRP activity is mediated by the G s -coupled G-protein-coupled receptor (GPCR), CRLR, which shares 55% homology with the calcitonin receptor. In an elegant study, McLatchie et al. (1) demonstrated that functional CGRP and adrenomedullin receptors are both derived from CRLR and that the phenotype i...