RO5256390 / Roche - LARVOL DELTA

Trace amine-associated receptors (TAARs)2-9 knockout mice exhibit reduced wakefulness and disrupted REM sleep. (PubMed, Front Psychiatry) - "High doses of the TAAR1 agonist RO5256390 increased wakefulness and reduced NREM sleep, while both RO5256390 and the partial agonist RO5263397 suppressed REM sleep in KO mice. These findings highlight the therapeutic potential of targeting TAARs 2-9 in sleep-related neuropsychiatric disorders. Further research is needed to elucidate their roles."

Journal • Preclinical • CNS Disorders • Mental Retardation • Psychiatry • Sleep Disorder

Is there a role for biogenic amine receptors in mediating β-phenylethylamine and RO5256390-induced vascular contraction? (PubMed, Eur J Pharmacol) - "Vasoconstrictor responses to trace amines are not mediated by classical biogenic amine neurotransmitter receptors. Insensitivity of β-PEA vasoconstrictor responses to EPPTB, may be explained by its low affinity for rat rather than murine TAAR1. Therefore, TAAR1 remains the most likely candidate receptor mediating vasoconstrictor responses to trace amines and that prazosin and yohimbine have low affinity for TAAR1."

Journal

Recognition of methamphetamine and other amines by trace amine receptor TAAR1. (PubMed, Nature) - "Here we report structures of human TAAR1-G protein complexes bound to METH and β-PEA as well as complexes bound to RO5256390, a TAAR1 selective agonist, and SEP-363856, a clinical-stage dual agonist for TAAR1 and serotonin receptor 5-HTR. We identify a lid-like ECL2 helix/loop structure and a hydrogen-bonding network in the ligand binding pockets, which may contribute to the ligand recognition in TAAR1. These findings shed light on the ligand recognition mode and activation mechanism for TAAR1 and should guide the development of next-generation therapeutics for drug addiction and various neurological disorders."

Journal • CNS Disorders • Depression • Psychiatry • Schizophrenia • Substance Abuse

Development of novel selective morpholine trace amine-associated receptor 1 partial agonists with promising preclinical effects related to neuropsychiatric disorders and well tolerated in healthy volunteers (Neuroscience 2023) - "TAAR1 agonists from a previous amino oxazolines series have been broadly studied preclinically (e.g. RO5263397, RO5256390, RO5203648) and in clinic (e.g. RO5263397)...We developed two selective partial agonists of TAAR1 (RO6889450 and RO6799477) and tested them extensively in nonclinical models predictive of antipsychotic, stress-response modulating and anti-addictive properties...Both compounds also showed a potentiation of the effect of olanzapine on PCP-induced hyperlocomotion in mice and a partial reversal of cocaïne-induced facilitation in intracranial self-stimulation threshold in rats...Both molecules have been investigated in Phase I single ascending dose (SAD) and multiple ascending dose (MAD) studies conducted in healthy volunteers to evaluate the safety, tolerability, PK, and pharmacodynamics. Based on its unique behavioral profile TAAR1 activation could represent a novel therapeutic option for neuropsychiatric disorders, including schizophrenia and..."

Preclinical • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Activation of trace amine-associated receptor 1 (TAAR1) transiently reduces alcohol drinking in socially housed mice. (PubMed, Addict Biol) - "Finally, we found that administration of RO5256390 may attenuate motivation for alcohol seeking. Taken together, our findings reveal that activation of TAAR1 may transiently reduce alcohol drinking; thus, TAAR1 is a promising target for the treatment of alcohol abuse and relapse."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry • Substance Abuse

Robust aversive effects of trace amine-associated receptor 1 activation in mice. (PubMed, Neuropsychopharmacology) - "Previous studies in a genetic mouse model of voluntary methamphetamine intake identified TAAR1, expressed by the Taar1 gene, as a critical mediator of aversive methamphetamine effects...Mice were tested for aversive effects of the selective TAAR1 agonist, RO5256390, using taste and place conditioning procedures...Our study provides important data on TAAR1 function in aversive, locomotor, and thermoregulatory effects that are important to consider when developing TAAR1 agonists as therapeutic drugs. Because other drugs can have similar consequences, potential additive effects should be carefully considered as these treatment agents are being developed."

Journal • Preclinical • CNS Disorders • Mental Retardation • Psychiatry

TAAR1 Regulates Purinergic-induced TNF Secretion from Peripheral, But Not CNS-resident, Macrophages. (PubMed, J Neuroimmune Pharmacol) - "The selective TAAR1 agonist RO5256390 was used in combination with common damage associated molecular patterns (ATP and ADP) to observe the effect of TAAR1 agonism on modulating cytokine secretion and metabolic profiles...In summary, we report a novel interaction between TAAR1 and purinergic signaling in peripherally-derived, but not CNS-resident, macrophages. These findings provide the first evidence of trace aminergic and purinergic crosstalk, and support the potential for TAAR1 as a novel therapeutic target in inflammatory disorders."

Journal • Immune Modulation • Immunology • Inflammation • IL6

Effects of acute and chronic administration of trace amine-associated receptor 1 (TAAR1) ligands on in vivo excitability of central monoamine-secreting neurons in rats. (PubMed, Mol Psychiatry) - "Full (e.g. RO5256390) and partial (e.g. RO5263397) TAAR1 agonists showed antidepressant-, antipsychotic- and anti-addiction-like behavioral effects in rodents and primates. Chronic RO5256390 increased excitability of 5-HT neurons of the DRN and dopamine neurons of the VTA. In conclusion, the putative antidepressant and antipsychotic effects of TAAR1 ligands might be mediated, at least in part, via the modulation of excitability of central 5-HT and dopamine neurons."

Journal • Preclinical • Anesthesia • CNS Disorders • Psychiatry

Trace Amine Associate Receptor 1 (TAAR1) as a New Target for the Treatment of Cognitive Dysfunction in Alzheimer's Disease. (PubMed, Int J Mol Sci) - "Thus, we studied, in vitro, the role of the TAAR1 agonist RO5256390 on basal cortical glutamatergic transmission and tested its effect on Aβ-induced dysfunction...Further studies are needed to better understand the interplay between TAAR1/Aβ and glutamatergic signalling, in order to evaluate the eventual beneficial effect in different experimental paradigms and animal models. Taken together, our data indicate that TAAR1 agonism may provide a novel therapeutic approach in the treatments of disorders involving Aβ-induced cognitive impairments, such as AD."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Trace amine-associated receptor 1 modulates motor hyperactivity, cognition, and anxiety-like behavior in an animal model of ADHD. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "administration of highly selective TAAR1 full agonist RO5256390 decreased motor hyperactivity, novelty-induced locomotion, and induced an anxiolytic-like behavior. Overall, our findings show that changes in TAAR1 levels/activity underlie behavior in SHR, suggesting that TAAR1 plays a role in the neurobiology of ADHD. Although additional confirmatory studies are required, TAAR1 might be a potential pharmacological target for individuals with this disorder."

Journal • Preclinical • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Mood Disorders • Psychiatry • Schizophrenia

Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders. (PubMed, CNS Drugs) - "Further, catecholamine metabolites and amphetamine analogs are also potent agonists of TAAR1, implicating the receptor in mediating the monoaminergic system and in substance use disorders. Selective and potent engineered TAAR1 ligands, including full (RO5166017 and RO5256390) and partial (RO5203648, RO5263397 and RO5073012) agonists and the antagonist EPPTB (N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl) benzamide, RO5212773), serve as invaluable tools for the investigation of TAAR1 functions and display significant potential for the development of TAAR1-based pharmacotherapies for the treatment of substance use disorders. Despite a number of advances that have been made, more clinical studies are warranted in order to test the potential and efficacy of TAAR1 ligands in the treatment of psychiatric disorders, including substance use disorders."

Journal • CNS Disorders • Mental Retardation • Psychiatry

Central and peripheral Methylamine-induced hypophagia is mediated via nitric oxide and TAAR in neonatal layer-type chicken. (PubMed, Neurosci Lett) - "Co-injection of the RO5256390 + MET amplified MET-induced hypophagia in FD chicken (P < 0.05). Based on the findings, MET-induced hypophagia is mediated via NO and TAAR pathways on food intake in layer chicken."

Journal • MET

Ligands of trace amine-associated receptor 1 modulate in vivo excitability of rat serotonin and dopamine, but not norepinephrine neurons. (ECNP 2019) - "After the last dose of RO5263397, 0.1 mg/kg of 8-OH-DPAT (for 5-HT neurons), yohimbine (for norepinephrine neurons), or haloperidol (for dopamine neurons) was administered. RO5256390, negatively modulates in vivo excitability of 5-HT and dopamine, but not norepinephrine neurons. It is consistent with reported inhibitory effects of RO5256390 [2] and of another TAAR1 agonist, RO5166017 [3], on the excitability of 5-HT and dopamine neurons and lack of their effect on norepinephrine neurons in brain slices, and with another study showing the presence of TAAR1 receptors in the DRN and VTA and their lack of presence in the LC [4]. The antidepressant-like and antipsychotic like behavioral effects of RO5256390 in laboratory animals, observed in a previous study [2], might be explained, at least in part, by its ability to modulate the excitability of 5-HT and dopamine neurons."

Preclinical

Trace amine associate receptor 1 (TAAR1) as a new target for the treatment of cognitive dysfunction in Alzheimer disease (ECNP 2019) - "...Cells were then stimulated with Ab 1-42 (1 µM, AnaSpec, USA), TAAR1 agonist (RO5256390, Sigma Aldrich, Belgium, 1 µM) or both 1hr at 37°C and NMDA surface expression was assessed using biotinylation assay and Western blots... Altogether, our results showed that in vitro, TAAR1 agonist displayed the ability of increasing NMDA receptors surface expression, suggesting the possibility of displaying therapeutic effect on cognitive Ab induced impairments. Whether these effects are reproducible in vivo, are currently addressed."

Interaction Between the Trace Amine-Associated Receptor 1 and the Dopamine D2 Receptor Controls Cocaine's Neurochemical Actions. (PubMed, Sci Rep) - "We show, first, that the full TAAR1 agonist, RO5256390, dose-dependently blocked cocaine-induced inhibition of DA clearance in slices of the nucleus accumbens. Predictably, inhibition of glycogen synthase kinase-3 (GSK-3), which results from activation of D2/TAAR1 heterodimers, fully reproduced the inhibitory effects of TAAR1 activation on cocaine-induced changes in DA transmission. Collectively, the present observations reveal that the ability of TAAR1 to regulate cocaine effects is linked to cooperative interactions with D2 autoreceptors and associated downstream molecular targets converging on GSK-3 and suggest a new mechanism to disrupt cocaine neurochemical actions."

Journal