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Novel selective morpholine trace amine-associated receptor 1 partial agonists show promising preclinical effects for neuropsychiatric disorders and are well tolerated in healthy volunteers

Molecular Psychiatry (2026)Cite this article

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Abstract

Trace amine-associated receptor 1 (TAAR1) is a novel target for antipsychotic and potentially mood-stabilizing and anti-addictive drugs, offering a new mechanism by modulating dopaminergic, serotonergic, and glutamatergic neurotransmission. TAAR1 agonists from a prior amino oxazolines series were studied preclinically and clinically, but development of partial agonist RO5263397 was halted due to poor metabolization by N-glucuronidation in individuals with UGT2B10 splice site mutations. A medicinal chemistry program subsequently identified new potent and selective TAAR1 ligands from the morpholine series. Two selective partial agonists, RO6799477 and RO6889450, were advanced and showed antipsychotic, stress-response-modulating, and anti-addictive-like activity in rodent models. They reduced PCP- and cocaine-induced hyperlocomotion, potentiated olanzapine’s effect, partially reversed cocaine-induced facilitation of intracranial self-stimulation and demonstrated anxiolytic-like properties in the stress-induced hyperthermia test. Neural activation profiles, measured by pharmacological MRI, differed from first and second-generation antipsychotics. Non-clinical drug abuse liability studies with RO6889450 indicated a favorable low abuse liability profile and suggested a lack of reinforcing effects. Preclinical safety studies indicated a favorable profile with clinically monitorable and reversible findings. Both compounds progressed into Phase I single and multiple ascending dose studies in healthy volunteers. RO6799477 was well tolerated, with rapid absorption and dose-proportional pharmacokinetics, though higher doses led to nervous system and cardiovascular adverse events. RO6889450 was well tolerated up to 300 mg; at 450 mg, dose-limiting adverse events included postural tachycardia and erythema. Together, these results indicate the translational potential and support further clinical exploration of TAAR1 agonists as a novel therapeutic option for neuropsychiatric disorders, particularly schizophrenia and substance use disorder.

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Fig. 1: Comparison of key TAAR1 compounds.
Fig. 2: RO6799477 and RO6889450 inhibit cocaine and NMDA receptor antagonist-induced hyperlocomotion in mice and potentiate the effect of Olanzapine.
Fig. 3: Modulation of the dopaminergic reward system by TAAR1 partial agonists in rats.

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Data availability

Information regarding the data and materials for this study is provided below: The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. Relevant data supporting the findings, including pharmacological profiles and pharmacokinetic parameters, are included within this article and its supplementary information files. Clinical trial data are registered and accessible via ClinicalTrials.gov under the identifiers NCT01893437, NCT02164266, and NCT02699372.

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Acknowledgements

We acknowledge the continuous support of F. Hoffmann-La Roche Ltd.

Funding

The work was funded by F. Hoffmann-La Roche Ltd.

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Authors and Affiliations

  1. Neuroscience and Rare Diseases, Therapeutic Modalities, Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070, Basel, Switzerland

    Céline Fournier, Danièle Buchy, Basil Kuennecke, Maddalena Marchesi, Stefan Holiga, Irene Gerlach & Marius C. Hoener

  2. Pharmaceutical Sciences, Therapeutic Modalities, Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070, Basel, Switzerland

    Susanne Mohr, Axel Pähler, Bjoern Jacobsen, Sabine Sewing, Andrea Greiter-Wilke, Christophe Schmitt & Mary Morrison

  3. Therapeutic Modalities, Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070, Basel, Switzerland

    Roger Norcross & Philippe Pflieger

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Contributions

CF contributed to the analysis and interpretation of data and drafted and revised the manuscript. DB contributed to the acquisition, analysis and interpretation of data and revised the manuscript. SM contributed to the conception and design of the work, the acquisition, analysis, and interpretation of data, and drafted and revised the manuscript. AP contributed to the conception and design of the work, the acquisition, analysis, and interpretation of data, and drafted and revised the manuscript. BJ contributed to the acquisition, analysis, and interpretation of data, and revised the manuscript. RN contributed to the conception and design of the work, the acquisition, analysis, and interpretation of data, and revised the manuscript. PP contributed to the acquisition, analysis, and interpretation of data. SS contributed to the analysis and interpretation of data. AGW contributed to the conception and design of the work, the acquisition, analysis, and interpretation of data, and drafted and revised the manuscript. BK contributed to the acquisition, analysis, and interpretation of data, and revised the manuscript. CS contributed to the acquisition, analysis, and interpretation of data, and revised the manuscript. MMo contributed to the acquisition, analysis, and interpretation of data, and revised the manuscript. MMa contributed to the acquisition, analysis, and interpretation of data, and revised the manuscript. SH revised the manuscript. IG revised the manuscript. MCH contributed to the conception and design of the work, the acquisition, analysis, and interpretation of data, and drafted and revised the manuscript.

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Correspondence to Marius C. Hoener.

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CF, DB, SM, AP, BJ, RN, PP, SS, AGW, BK, CS, MM, MM, SH, IG and MCH are employees of F. Hoffmann-La Roche, Ltd. and may own stock or stock options.

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Fournier, C., Buchy, D., Mohr, S. et al. Novel selective morpholine trace amine-associated receptor 1 partial agonists show promising preclinical effects for neuropsychiatric disorders and are well tolerated in healthy volunteers. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03465-y

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