Abstract
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. In addition to TAAR1 agonism, ulotaront is a partial agonist at the serotonin 1A receptor (5-HT1AR). However, little is publicly known about ralmitaront. We compared ulotaront and ralmitaront at TAAR1, 5-HT1AR, and D2R using luciferase complementation-based G protein recruitment, cAMP accumulation, and GIRK channel activation assays. Ralmitaront showed lower efficacy at TAAR1 in G protein recruitment, cAMP accumulation, and GIRK activation assays. Moreover, ralmitaront lacked detectable activity at 5-HT1AR and D2R. Compared to ulotaront, ralmitaront shows lower efficacy and slower kinetics at TAAR1, and lacks efficacy at 5-HT1AR. These data may be relevant to understanding differences in clinical profiles of these two compounds.
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