The Action of TAAR1 Agonist RO5263397 on Executive Functions in Rats

Dorotenko, Artem; Tur, M.; Dolgorukova, Antonina; Бортников, Н. С.; Belozertseva, Irina; Zvartau, Edwin; Gainetdinov, Raul R.; Sukhanov, I.

doi:10.1007/s10571-019-00757-6

Cited by 14 publications

(3 citation statements)

References 46 publications

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“…Interestingly, it was found that TAAR1 agonists also exhibit useful properties for the treatment of depression [ 31 ]. For instance, TAAR1 agonists RO5256390, RO5203648, and RO5263397, in addition to antipsychotic actions, have demonstrated in vivo improvement in the sleep–wake cycle [ 85 , 86 ], reduction in drug cravings [ 87 , 88 ], and procognitive properties [ 89 , 90 , 91 ]. The direct antidepressant potential is indicated by work on the forced swimming test in rodents.…”

Section: The Family Of Taars—a New Target For Depression Therapy?mentioning

confidence: 99%

TAARs as Novel Therapeutic Targets for the Treatment of Depression: A Narrative Review of the Interconnection with Monoamines and Adult Neurogenesis

Shemiakova,

Efimova,

Gainetdinov

2024

Biomedicines

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Depression is a common mental illness of great concern. Current therapy for depression is only suitable for 80% of patients and is often associated with unwanted side effects. In this regard, the search for and development of new antidepressant agents remains an urgent task. In this review, we discuss the current available evidence indicating that G protein-coupled trace amine-associated receptors (TAARs) might represent new targets for depression treatment. The most frequently studied receptor TAAR1 has already been investigated in the treatment of schizophrenia, demonstrating antidepressant and anxiolytic properties. In fact, the TAAR1 agonist Ulotaront is currently undergoing phase 2/3 clinical trials testing its safety and efficacy in the treatment of major depressive disorder and generalized anxiety disorder. Other members of the TAAR family (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9) are not only involved in the innate olfaction of volatile amines, but are also expressed in the limbic brain areas. Furthermore, animal studies have shown that TAAR2 and TAAR5 regulate emotional behaviors and thus may hold promise as potential antidepressant targets. Of particular interest is their connection with the dopamine and serotonin systems of the brain and their involvement in the regulation of adult neurogenesis, known to be affected by the antidepressant drugs currently in use. Further non-clinical and clinical studies are necessary to validate TAAR1 (and potentially other TAARs) as novel therapeutic targets for the treatment of depression.

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Section: The Family Of Taars—a New Target For Depression Therapy?mentioning

confidence: 99%

TAARs as Novel Therapeutic Targets for the Treatment of Depression: A Narrative Review of the Interconnection with Monoamines and Adult Neurogenesis

Shemiakova,

Efimova,

Gainetdinov

2024

Biomedicines

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“…Based on the preclinical studies, it might be expected that TAAR1 could be a potential drug target for several neuropsychiatric disorders, including schizophrenia, depression, bipolar disorder, generalized anxiety disorder, addiction, ADHD, Alzheimer's disorder, etc. [29,[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52].…”

Section: Introductionmentioning

confidence: 99%

Unlocking the Therapeutic Potential of Ulotaront as a Trace Amine-Associated Receptor 1 Agonist for Neuropsychiatric Disorders

et al. 2023

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All antipsychotics currently used in clinic block D2 dopamine receptors. Trace amine-associated receptor 1 is emerging as a new therapeutic target for schizophrenia and several other neuropsychiatric disorders. SEP-363856 (International Nonproprietary Name: Ulotaront) is an investigational antipsychotic drug with a novel mechanism of action that does not involve antagonism of dopamine D2 receptors. Ulotaront is an agonist of trace amine-associated receptor 1 and serotonin 5-HT1A receptors, but can modulate dopamine neurotransmission indirectly. In 2019, the United States Food and Drug Administration granted Breakthrough Therapy Designation for ulotaront for the treatment of schizophrenia. Phase 2 clinical studies indicated that ulotaront can reduce both positive and negative symptoms of schizophrenia without causing the extrapyramidal or metabolic side effects that are inherent to most currently used antipsychotics. At present, it is in phase 3 clinical development for the treatment of schizophrenia and is expected to be introduced into clinical practice in 2023–2024. Clinical studies evaluating the potential efficacy of ulotaront in Parkinson’s disease psychosis, generalized anxiety disorder, and major depressive disorder have also been started. The aim of this scoping review is to summarize all currently available preclinical and clinical evidence on the utility of ulotaront in the treatment of schizophrenia. Here, we show the main characteristics and distinctive features of this drug. Perspectives and limitations on the potential use of ulotaront in the pharmacotherapy of several other neuropsychiatric disorders are also discussed.

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“…In the brain, TAAR1 proved to be an important modulator of the major monoamine (dopamine and serotonin) and glutamate signaling pathways, directing the attention of researchers on the therapeutic implications of TAAR1 ligands in neuropsychiatric disorders [3,12,13]. The pharmaceutical company Hoffmann-La Roche was an early leader in TAAR1 drug discovery and registered several patents [14] as well as published preclinical studies [15][16][17][18][19] with selective TAAR1 agonists. TAAR1 agonists now give promise to be a new generation of antipsychotic medications, as evidenced by two compounds that have entered clinical trials, SEP-363856 (ulotaront-Sunovion) and RO6889450 (ralmitaront-La Roche) [13,20,21].…”

Section: Introductionmentioning

confidence: 99%

Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays

Cichero,

Francesconi,

Casini

et al. 2023

Pharmaceuticals

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Trace amine-associated receptor 1 (TAAR1) is an attractive target for the design of innovative drugs to be applied in diverse pharmacological settings. Due to a non-negligible structural similarity with endogenous ligands, most of the agonists developed so far resulted in being affected by a low selectivity for TAAR1 with respect to other monoaminergic G protein-coupled receptors, like the adrenoreceptors. This study utilized comparative molecular docking studies and quantitative–structure activity relationship (QSAR) analyses to unveil key structural differences between TAAR1 and alpha2-adrenoreceptor (α2-ADR), with the aim to design novel TAAR1 agonists characterized by a higher selectivity profile and reduced off-target effects. While the presence of hydrophobic motives is encouraged towards both the two receptors, the introduction of polar/positively charged groups and the ligand conformation deeply affect the TAAR1 or α2-ADR putative selectivity. These computational methods allowed the identification of the α2A-ADR agonist guanfacine as an attractive TAAR1-targeting lead compound, demonstrating nanomolar activity in vitro. In vivo exploration of the efficacy of guanfacine showed that it is able to decrease the locomotor activity of dopamine transporter knockout (DAT-KO) rats. Therefore, guanfacine can be considered as an interesting template molecule worthy of structural optimization. The dual activity of guanfacine on both α2-ADR and TAAR1 signaling and the related crosstalk between the two pathways will deserve more in-depth investigation.

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The Action of TAAR1 Agonist RO5263397 on Executive Functions in Rats

Cited by 14 publications

References 46 publications

TAARs as Novel Therapeutic Targets for the Treatment of Depression: A Narrative Review of the Interconnection with Monoamines and Adult Neurogenesis

TAARs as Novel Therapeutic Targets for the Treatment of Depression: A Narrative Review of the Interconnection with Monoamines and Adult Neurogenesis

Unlocking the Therapeutic Potential of Ulotaront as a Trace Amine-Associated Receptor 1 Agonist for Neuropsychiatric Disorders

Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays

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