In Vitro Comparison of Ulotaront (SEP-363856) and Ralmitaront (RO6889450): Two TAAR1 Agonist Candidate Antipsychotics

BACKGROUND: Trace amine-associated receptor-1 (TAAR1) agonists have been proposed as potential antipsychotics, with ulotaront and ralmitaront having reached clinical trials. While ulotaront demonstrated efficacy in a recent Phase II trial, a corresponding study studies of ralmitaront failed to show efficacy as a monotherapy or as an adjunct to atypical antipsychotics. In addition to TAAR1 agonism, ulotaront is a partial agonist at the serotonin 1A receptor (5-HT(1A)R). However, little is known about ralmitaront. METHODS: We compared ulotaront and ralmitaront at TAAR1, 5-HT(1A)R, and dopamine D(2) using luciferase complementation-based G protein recruitment, cAMP accumulation, and G protein–coupled inward rectifier potassium channel activation assays. RESULTS: Ralmitaront showed lower efficacy at TAAR1 in G protein recruitment, cAMP accumulation, and GIRK activation assays. Moreover, ralmitaront lacked detectable activity at 5-HT(1A)R and dopamine D(2). CONCLUSIONS: Compared with ulotaront, ralmitaront shows lower efficacy and slower kinetics at TAAR1 and lacks efficacy at 5-HT(1A)R. These data may be relevant to understanding differences in clinical profiles of these 2 compounds.