RO5263397 / Roche, SRI International - LARVOL DELTA

Preclinical development of [18F]TAAR1-2203 as a PET radioligand for imaging TAAR1 expression and receptor occupancy. (PubMed, Eur J Nucl Med Mol Imaging) - "[18F]TAAR1-2203 represents the first PET radioligand for TAAR1 imaging with favorable in vitro and in vivo performance characteristics, enabling non-invasive assessment of receptor expression and drug occupancy in peripheral TAAR1-expressing tissues. [18F]TAAR1-2203 holds promise for translational application in various drug development programs."

Journal • Preclinical • Metabolic Disorders • Psychiatry

The anticonvulsant activity of trace amine-associated receptor 1 (TAAR1) agonists involves GABAB receptors in mice. (PubMed, Eur J Pharmacol) - "We therefore investigated the effects of TAAR1 agonists on acute seizures induced by continuous intravenous infusion of a GABAA receptor antagonist, pentylenetetrazol (PTZ), and an inhibitor of voltage-gated potassium channels, 4-aminopyridine (4-AP), in mice. The TAAR1 agonists RO5263397 and RO5256390 did not affect the threshold dose for PTZ-induced seizures; however, they significantly increased the threshold for 4-AP-induced seizures. The anticonvulsant activities of these TAAR1 agonists were blocked by intracerebroventricular administration of CGP 35348, a GABAB receptor antagonist. These results suggest that GABAB receptors are involved in the anticonvulsant effects of TAAR1 agonists."

Journal • Preclinical • CNS Disorders • Epilepsy • Mental Retardation • Psychiatry • Schizophrenia

TAAR1 in the mediodorsal thalamus is involved in the enhancement of fear memory after social defeat in mice (CINP-AsCNP 2025) - "Chronic social defeat stress leads to enhanced fear memory and reduced expression of TAAR1 in the MD. Specifically, manipulating TAAR1 levels in the MD can mimic or reverse the negative effects caused by stress. Both systematic and specific MD administration of the TAAR1 partial agonist RO5263397 effectively improves stress-induced increased contextual fear memory."

Preclinical • CNS Disorders • Cognitive Disorders • Mental Retardation • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Trace Amine-Associated Receptor 1 agonists reduce alcohol drinking and differentially modulate dopamine release in the nucleus accumbens of alcohol preferring mice. (PubMed, Neuropharmacology) - "In this study, we evaluated the effects of the full agonist RO5166017 and the partial agonist RO5263397 on alcohol consumption using an intermittent access protocol in alcohol-preferring male C57BL/6JRj mice...Our findings highlight the therapeutic potential of TAAR1 agonists for alcohol addiction and reveal important functional differences between full and partial agonists. Further research is needed to determine the clinical relevance of these distinct pharmacodynamic profiles and optimize TAAR1-targeting pharmacotherapies."

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

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

Wakefulness Induced by TAAR1 Partial Agonism is Mediated Through Dopaminergic Neurotransmission. (PubMed, bioRxiv) - "Male C57BL6/J mice (n=8) were intraperitoneally administered the D1R antagonist SCH23390, the D2R antagonist eticlopride, a combination of D1R+D2R antagonists or saline at ZT5.5, followed 30 min later by RO5263397 or vehicle (10% DMSO in DI water) at ZT6 per os . These results suggest that, whereas TAAR1 effects on wakefulness are mediated in part through the D2R, D1R activation plays a role in reversing the TAAR1-mediated increase in NREM sleep latency. By contrast, TAAR1-mediated suppression of REM sleep appears not to involve D1R or D2R mechanisms."

Journal • Sleep Disorder

Vibrational spectroscopic interpretation, solvent effect and molecular docking studies of TAAR1 partial agonist RO5263397. (PubMed, Spectrochim Acta A Mol Biomol Spectrosc) - "The existence of hydrogen bonding is validated by reactive site findings from Mulliken atomic charge distribution and molecule electrostatic potential surface studies. Information about distinct drug-receptor interactions obtained from molecular docking investigation offers the path of further study of molecular activity in various drug-receptor mechanism."

Journal

TAAR1 and 5-HT1B receptor agonists attenuate autism-like irritability and aggression in rats prenatally exposed to valproic acid. (PubMed, Pharmacol Biochem Behav) - "Single administration of the 5-HT1B agonist CP-94253 or TAAR1 agonist RO5263397 attenuated the frustration-like behavior compared to vehicle...Our study describes previously uncharacterized phenotypes of frustration, irritability, and aggression in the rat prenatal VPA model of ASD. Administration of selective TAAR1 or 5-HT1B receptor agonists alleviated these deficits, warranting further exploration of both targets in ASD treatment."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Genetic Disorders

Vasoconstrictor Effects of Trace Amine Associated Receptor Agonists in the Isolated Perfused Rat Kidney. (PubMed, Med Princ Pract) - "The agonist-induced increase in perfusion pressure in the kidney involves the influx of extracellular calcium, increased calcium sensitization, and ROS in SHRs only."

Journal • Preclinical

The versatile binding landscape of the TAAR1 pocket for LSD and other antipsychotic drug molecules. (PubMed, Cell Rep) - "This study presents structures of the TAAR1-Gs protein complex recognizing LSD, which exhibits a polypharmacological profile, and the partial agonist RO5263397, which is a drug candidate for schizophrenia and addiction...Through mutagenesis, functional studies, and molecular dynamics (MD) simulations, we provide a comprehensive understanding of a versatile TAAR1 pocket in recognizing various ligands as well as in the ligand-free state, underpinning the structural basis of its high adaptability. These findings offer valuable insights for the design of antipsychotic drugs."

Journal • CNS Disorders • Psychiatry • Schizophrenia

Activation of trace amine-associated receptor 1 ameliorates PTSD-like symptoms. (PubMed, Biochem Pharmacol) - "Acute treatment of the TAAR1 partial agonist RO5263397 attenuated SPS-induced anxiety-like behavior evaluated by the elevated-plus maze test...Taken together, these data showed that pharmacological activation of TAAR1 could ameliorate PTSD-like symptoms. The present study thus provides the first evidence that TAAR1 might participate in the development of PTSD, and TAAR1 agonists could be potential pharmacological treatments for this disorder."

Journal • CNS Disorders • Mental Retardation • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Dopamine D1 receptor in medial prefrontal cortex mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits. (PubMed, Neuropsychopharmacology) - "Using pharmacological interventions, we found that D1R antagonist disrupted therapeutic effect of TAAR1 partial agonist RO5263397 on stress-related cognitive and social dysfunction. Knockout TAAR1 in D1-type dopamine receptor-expressing neurons reproduced adverse effects of chronic stress, and TAAR1 conditional knockout in the mPFC led to similar deficits, along with downregulation of D1R expression, all of these effects were ameliorated by viral overexpression of D1R in the mPFC, suggesting the functional interaction between TAAR1 and D1R. Collectively, our data elucidate the possible molecular mechanism that D1R in the mPFC mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits."

Journal

TAAR1 in dentate gyrus is involved in chronic stress-induced impairments in hippocampal plasticity and cognitive function. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "Importantly, the administration of the selective TAAR1 partial agonist RO5263397 during stress exposure attenuated the adverse effects of chronic stress on cognitive function, adult neurogenesis, dendritic arborization, and the synapse number of dentate neurons in DG. In summary, our findings suggest that TAAR1 plays a crucial role in mediating the detrimental effects of chronic stress on hippocampal plasticity and cognition. TAAR1 agonists exhibit therapeutic potential for individuals suffering from cognitive impairments associated with MDD."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

TAAR1 Agonists Improve Glycemic Control, Reduce Body Weight and Modulate Neurocircuits Governing Energy Balance and Feeding. (PubMed, Mol Metab) - "The current data demonstrate that TAAR1 agonists, as a class, not only lack APD-induced metabolic liabilities but can reduce body weight and improve glycemic control in rodent models. The underlying mechanisms likely include TAAR1-mediated peripheral effects on glucose homeostasis and gastric emptying as well as central regulation of energy balance and food intake."

Journal • CNS Disorders • Genetic Disorders • Metabolic Disorders • Obesity • Psychiatry • Schizophrenia • FOS

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

Vasodilator Effect of Trace Amines, 3-Iodothyronamine, and RO5263397 in the Rat Perfused Kidney: Comparison with Tryptamine. (PubMed, Pharmacology) - "It was concluded that vasodilator responses produced by the TAAR1 agonists, T1AM, RO5263397, and tryptamine, were not mediated via TAAR1 but were probably via activation of 5-HT1A receptors."

Journal • Preclinical

Contribution of UGT Enzymes to Human Drug Metabolism Stereoselectivity: A Case Study of Medetomidine, RO5263397, Propranolol, and Testosterone. (PubMed, Drug Metab Dispos) - "However, translation from in vitro to in vivo can be challenging as contributions from multiple enzymes and enzyme classes must be combined with protein binding and blood/plasma partitioning data to estimate the net intrinsic clearance for each enantiomer. Preclinical species may be misleading as enzyme involvement and metabolism stereoselectivity can differ substantially."

Journal

Selective TAAR1 agonists induce conditioned taste aversion. (PubMed, Psychopharmacology (Berl)) - "Taken together, our data indicate that selective TAAR1 agonists could produce strong CTA. Our study urges careful evaluations of the aversive effects of TAAR1 agonists before translating them to clinical use for the treatment of mental disorders."

Journal • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

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

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

The selective TAAR1 partial agonist RO5263397 promoted novelty recognition memory in mice. (PubMed, Psychopharmacology (Berl)) - "These results indicate that TAAR1 activation promotes NOR memory retrieval. Consistent with previous studies, our finding further suggests that TAAR1 agonists have pro-cognitive properties."

Journal • Preclinical

Differential effects of β-methylphenylethylamine and octopamine on contractile parameters of the rat gastrointestinal tract. (PubMed, Eur J Pharmacol) - "β-MPEA-induced contractions in rat gastric fundus strips under resting tonus conditions, but induced relaxation in preparations that were previously contracted with carbachol...Contrarily, EPPTB did not reduce the relaxant effects of RO5263397 (TA agonist) or zacopride (5-HT agonist)...Octopamine inhibited the rat gut contractility through the likely involvement of 5-HT and TA receptors. Overall, octopamine effectively inhibited rat gastrointestinal transit."

Journal • Preclinical • Gastrointestinal Disorder

Activation of trace amine-associated receptor 1 attenuates nicotine withdrawal-related effects. (PubMed, Addict Biol) - "TAAR1 partial agonist RO5263397 significantly reduced the physical and motivational withdrawal effects of nicotine in LA rats, as reflected by increased time spent on the open arm in the elevated plus maze (EPM) test, normalized paw withdrawal threshold, decreased withdrawal signs and motivation to self-administer nicotine. This study indicates that activation of TAAR1 attenuates the negative-reinforcing effects of nicotine withdrawal and further suggests TAAR1 as a promising target to treat nicotine addiction."

Journal • CNS Disorders • Immunology • Mood Disorders • Nicotine Addiction • Psychiatry

TAAR1 and Psychostimulant Addiction. (PubMed, Cell Mol Neurobiol) - "We also discuss several concerns including the abuse liability, sleep reduction, and species-dependent effects that might affect the successful translation of TAAR1 agonists from preclinical studies to clinical application. In conclusion, although further investigations are in need to address certain concerns and the underlying neural mechanisms, TAAR1 agonists appear to be a promising pharmacotherapy to treat psychostimulant addiction and prevent relapse."

Journal • CNS Disorders • Psychiatry

[VIRTUAL] Modeling Parkinson’s disease on trace amine-associated receptor 5 knockout mice (ECNP 2020) - "For TAAR1 agonists it was also shown that they aggravated degeneration induced by 6-OHDA in WT mice and subchronic treatment by L-DOPA of 6-OHDA model of TAAR1-KO mice resulted in more pronounced rotational behavior in their wild type counterparts... We find differences in 6-OHDA model on TAAR- knockout mice and this study will be continued to exam the role of TAARs in pathogenesis of the Parkinson’s disease."

Preclinical • CNS Disorders • Parkinson's Disease