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

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.

Discovery of Trace Amine Associated Receptor 1 (TAAR1) Agonist 2-(5-(4'-Chloro-[1,1'-biphenyl]-4-yl)-4H-1,2,4-triazol-3-yl)ethan-1-amine (LK00764) for the Treatment of Psychotic Disorders.

A focused in-house library of about 1000 compounds comprising various heterocyclic motifs in combination with structural fragments similar to ß-phenethylamine (PEA) or tyramine was screened for the agonistic activity towards trace amine-associated receptor 1 (TAAR1). The screening yielded two closely related hits displaying EC50 values in the upper submicromolar range. Extensive analog synthesis and testing for TAAR1 agonism in a BRET-based cellular assay identified compound 62 (LK00764) with EC50 = 4.0 nM. The compound demonstrated notable efficacy in such schizophrenia-related in vivo tests as MK-801-induced hyperactivity and spontaneous activity in rats, locomotor hyperactivity of dopamine transporter knockout (DAT-KO) rats, and stress-induced hyperthermia (i.p. administration). Further preclinical studies are necessary to evaluate efficacy, safety and tolerability of this potent TAAR1 agonist for the potential development of this compound as a new pharmacotherapy option for schizophrenia and other psychiatric disorders.

Discovery and In Vivo Efficacy of Trace Amine-Associated Receptor 1 (TAAR1) Agonist 4-(2-Aminoethyl)-N-(3,5-dimethylphenyl)piperidine-1-carboxamide Hydrochloride (AP163) for the Treatment of Psychotic Disorders.

Starting from a screening hit, a set of analogs was synthesized based on a 4-(2-aminoethyl)piperidine core not associated previously with trace amine-associated receptor 1 (TAAR1) modulation in the literature. Several structure-activity relationship generalizations have been drawn from the observed data, some of which were corroborated by molecular modeling against the crystal structure of TAAR1. The four most active compounds (EC50 for TAAR1 agonistic activity ranging from 0.033 to 0.112 µM) were nominated for evaluation in vivo. The dopamine transporter knockout (DAT-KO) rat model of dopamine-dependent hyperlocomotion was used to evaluate compounds' efficacy in vivo. Out of four compounds, only one compound (AP163) displayed a statistically significant and dose-dependent reduction in hyperlocomotion in DAT-KO rats. As such, compound AP163 represents a viable lead for further preclinical characterization as a potential novel treatment option for disorders associated with increased dopaminergic function, such as schizophrenia.

Tumor targeting using magnetic nanoparticle Hsp70 conjugate in a model of C6 glioma.

BACKGROUND: Superparamagnetic iron oxide nanoparticles (SPIONs), due to their unique magnetic properties, have the ability to function both as magnetic resonance (MR) contrast agents, and can be used for thermotherapy. SPIONs conjugated to the heat shock protein Hsp70 that selectively binds to the CD40 receptor present on glioma cells, could be used for MR contrast enhancement of experimental C6 glioma. METHODS: The magnetic properties of the Hsp70-SPIONs were measured by NMR relaxometry method. The uptake of nanoparticles was assessed on the C6 glioma cells by confocal and electron microscopes. The tumor selectivity of Hsp70-SPIONs being intravenously administered was analyzed in the experimental model of C6 glioma in the MRI scanner. RESULTS: Hsp70-SPIONs relaxivity corresponded to the properties of negative contrast agents with a hypointensive change of resonance signal in MR imaging. A significant accumulation of the Hsp70-SPIONs but not the non-conjugated nanoparticles was observed by confocal microscopy within C6 cells. Negative contrast tumor enhancement in the T2-weighted MR images was higher in the case of Hsp70-SPIONs in comparison to non-modified SPIONs. Histological analysis of the brain sections confirmed the retention of the Hsp70-SPIONs in the glioma tumor but not in the adjacent normal brain tissues. CONCLUSION: The study demonstrated that Hsp70-SPION conjugate intravenously administered in C6 glioma model accumulated in the tumors and enhanced the contrast of their MR images.