In vitro comparison of ulotaront (SEP-363856) and ralmitaront (RO6889450): two TAAR1 agonist candidate antipsychotics

Ågren, RichardDepartment of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden (author)

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-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.

Betari, NibalUmeå universitet,Institutionen för integrativ medicinsk biologi (IMB),Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM)(Swepub:umu)nibe0134 (author)
Saarinen, MarcusDepartment of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden (author)
Zeberg, HugoKarolinska Institutet (author)
Svenningsson, PerDepartment of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden; Basal and Clinical Neuroscience, Institute of Psychiatry, King's College London, Psychology and Neuroscience, London, United Kingdom (author)
Sahlholm, KristofferUmeå universitet,Institutionen för integrativ medicinsk biologi (IMB),Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden(Swepub:umu)krsa0055 (author)
Department of Physiology and Pharmacology, Karolinska Institutet, Solna, SwedenInstitutionen för integrativ medicinsk biologi (IMB) (creator_code:org_t)

In:International Journal of Neuropsychopharmacology: Oxford University Press26:9, s. 599-6061461-14571469-5111

By the author/editor: Ågren, Richard; Betari, Nibal; Saarinen, Marcus; Zeberg, Hugo; Svenningsson, Pe ...; Sahlholm, Kristo ...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Pharmacology and ...

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