Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia

Abstract

Ulotaront (SEP-363856) is a trace-amine associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity in Phase 3 clinical development, with FDA Breakthrough Therapy Designation, for the treatment of schizophrenia. TAAR1 is a G-protein-coupled receptor (GPCR) that is expressed in cortical, limbic, and midbrain monoaminergic regions. It is activated by endogenous trace amines, and is believed to play an important role in modulating dopaminergic, serotonergic, and glutamatergic circuitry. TAAR1 agonism data are reported herein for ulotaront and its analogues in comparison to endogenous TAAR1 agonists. In addition, a human TAAR1 homology model was built around ulotaront to identify key interactions and attempt to better understand the scaffold-specific TAAR1 agonism structure–activity relationships.

Public Transcriptomic Data Meta-Analysis Demonstrates TAAR6 Expression in the Mental Disorder-Related Brain Areas in Human and Mouse Brain

“…In a similar public data study [ 49 ], we also found that the level of TAAR5 expression was higher than that observed for TAAR6 in the present study. It should also be mentioned that despite the similarly low level of expression of TAAR1, the agonist of this receptor, Ulotaront, showed clinical efficacy in patients with schizophrenia, ameliorating both positive and negative symptoms without causing side effects of currently used antipsychotics [ 67 , 68 , 69 , 70 ].…”

Applying a Fast-Scan Cyclic Voltammetry to Explore Dopamine Dynamics in Animal Models of Neuropsychiatric Disorders

“…In fact, TAAR1 agonists effectively inhibit hyperactivity of DAT-KO animals [35,[137][138][139]. In clinical trials, the first tested TAAR1 agonist with 5-HT1A agonist activity Ulotaront showed significant efficacy in treating patients with schizophrenia on both positive and negative symptoms without causing the side effects of existing antipsychotics [140]. Ulotaront emerges as the first representative of new generation of antipsychotics not directly affecting D2 dopamine receptor function.…”

Risk of Drug-induced Movement Disorders with Newer Antipsychotic Agents

“…Three novel classes of antipsychotics are currently under investigation whose mechanisms of action have the potential to obviate DIMD. Uloturant, a trace amine-associated receptor 1 (TAAR1) agonist, is currently in Phase 3 clinical trials for schizophrenia [ 142 ]. TAAR1s are G-protein coupled receptors expressed in multiple brain regions including the ventral tegmental area and the dorsal raphe nucleus, which allow for modulation of dopaminergic and serotonergic pathways improving positive schizophrenic symptoms and sleep [ 142 ].…”

“…Uloturant, a trace amine-associated receptor 1 (TAAR1) agonist, is currently in Phase 3 clinical trials for schizophrenia [ 142 ]. TAAR1s are G-protein coupled receptors expressed in multiple brain regions including the ventral tegmental area and the dorsal raphe nucleus, which allow for modulation of dopaminergic and serotonergic pathways improving positive schizophrenic symptoms and sleep [ 142 ]. While it has agonist activity at 5-HT 1A Rs, it does not have antagonism at D2 or 5-HT 2A Rs which is thought to improve its tolerability [ 142 ].…”

“…TAAR1s are G-protein coupled receptors expressed in multiple brain regions including the ventral tegmental area and the dorsal raphe nucleus, which allow for modulation of dopaminergic and serotonergic pathways improving positive schizophrenic symptoms and sleep [ 142 ]. While it has agonist activity at 5-HT 1A Rs, it does not have antagonism at D2 or 5-HT 2A Rs which is thought to improve its tolerability [ 142 ]. Early studies have not shown a risk of DIMD as expected from data in preclinical models with AEs most commonly being somnolence and GI symptoms [ 143 ].…”