Review of the TAAR1 Agonist Ulotaront: Part I-From Discovery to Clinic

Abstract Introduction Trace amine-associated receptors (TAARs) are a family of G-protein-coupled receptors (GPCRs) first identified in 2001. TAAR1 has emerged as a promising therapeutic target due to its ability to modulate monoaminergic and glutamatergic neurotransmission. Ulotaront is a trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity that has received FDA Breakthrough Therapy Designation for the treatment of schizophrenia. Here we provide a brief review of the discovery of ulotaront and preclinical research suggesting efficacy in schizophrenia, leading to the first clinical trial of ulotaront resulting in FDA Breakthrough Therapy Designation. Methods Ulotaront was discovered through a target-agnostic approach optimized to identify drug candidates that demonstrate an antipsychotic-like profile in vivo but lack D2 and 5-HT2A receptor antagonism. Ulotaront was further characterized by in vitro pharmacology, electrophysiology, behavioral, and imaging studies. Results Ulotaront demonstrated an antipsychotic-like profile in a high-throughput, phenotypic behavior screening platform, as well as efficacy in preclinical models of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition of acoustic startle, and subchronic PCP-induced deficits in social interaction. Although not fully elucidated, ulotaront’s mechanism of action appears to be mediated by agonism at trace amine-associated 1 (TAAR1) and 5-HT1A receptors. This was further corroborated with whole cell patch clamp recordings, demonstrating inhibition of dorsal raphe nucleus (DRN) and ventral tegmental area (VTA) neuronal firing via 5-HT1A and TAAR1 receptors. Furthermore, ulotaront attenuated the ketamine-induced increase in striatal dopamine synthesis capacity, suggesting that it may modulate presynaptic dopamine dysfunction which is hypothesized to contribute to the pathophysiology of schizophrenia. Conclusions Preclinical studies have identified ulotaront as a TAAR1 agonist with antipsychotic-like activity. Ulotaront’s unique receptor profile led to its designation as a member of the new “-taront” class of TAAR1 agonists, distinct in pharmacology from the D2/5-HT2A class of antipsychotics. A companion poster will summarize the efficacy and safety of ulotaront based on initial clinical trials in schizophrenia. Funding Sunovion Pharmaceuticals, Inc., and Otsuka Pharmaceutical Development & Commercialization, Inc.