2. Academic Validation
  3. In Vitro Comparison of Ulotaront (SEP-363856) and Ralmitaront (RO6889450): Two TAAR1 Agonist Candidate Antipsychotics

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

  • Int J Neuropsychopharmacol. 2023 Sep 25;26(9):599-606. doi: 10.1093/ijnp/pyad049.
Richard Ågren 1,  Nibal Betari 2,  Marcus Saarinen 3,  Hugo Zeberg 1,  Per Svenningsson 4 3,  Kristoffer Sahlholm 1 2
Affiliations

Affiliations

  • 1 Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden.
  • 2 Department of Integrative Medical Biology, Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
  • 3 Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden.
  • 4 Basal and Clinical Neuroscience, Institute of Psychiatry, King's College London, Psychology and Neuroscience, London, UK.
PMID: 37549917 DOI: 10.1093/ijnp/pyad049
Abstract

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-HT1AR). However, little is known about ralmitaront.

Methods: We compared ulotaront and ralmitaront at TAAR1, 5-HT1AR, and dopamine D2 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-HT1AR and dopamine D2.

Conclusions: Compared with 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 2 compounds.

Keywords

Trace amine-associated receptor-1; dopamine D2 receptor; electrophysiology; luminescence measurements; serotonin 1A receptor.

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