189. A novel TAAR1 and 5-HT1AR dual agonist with broad psychotropic effects

Abstract

Abstract Background Psychosis, characterized by delusions and hallucinations, is a hallmark of schizophrenia and bipolar disorder and is also observed in neurodegenerative diseases such as Alzheimer’s disease and Dementia with Lewy Bodies. Currently available treatment options primarily rely on antagonism of dopamine D2 receptors and while these agents alleviate positive symptoms, their clinical utility is limited by a range of adverse effects, including extrapyramidal symptoms and metabolic disturbances. The trace amine associated receptor 1 (TAAR1), in combination with the 5-HT1A receptor, has emerged as an alternative potential therapeutic target for psychotic symptoms, largely supported by recent clinical evidence. Analyses including both pre-clinical and clinical data suggest that the combination of TAAR1 and 5-HT1AR is superior in terms of safety compared to atypical antipsychotics. Here, we report a novel compound possessing TAAR1 and 5-HT1AR agonism and its antipsychotic potential in multiple preclinical behavioural assays. Aims & Objectives In this current presentation, we sought to demonstrate the efficacy of our novel compound in commonly used models of psychosis and other behaviours, and to evaluate its translational potential in multiple assays in vivo. Method Male C57BL/6 mice and Sprague Dawley rats were used for experiments unless stated otherwise. All studies were conducted following previously reported methods. Antipsychotic effects were evaluated on the Phencyclidine (PCP) hyperactivity test using mice, anxiolytic effects were tested on the contextual fear conditioning paradigm using rats, and antidepressant properties were assessed on the forced swimming test using Wistar Kyoto rats. The microdialysis experiment was performed on rats and quantified using HPLC and MS/MS. Electrophysiological recordings of ventral tegmental area neurons were performed on acute mouse brain slices under bath application of compounds. For the translational experiments, gastric emptying was assessed using the acetaminophen test in mice, and sleep architecture was evaluated in rats utilizing EEG/EMG recordings. Results The novel dual agonist significantly reduced hyperlocomotion in the PCP-induced hyperlocomotion test, freezing time in the contextual fear conditioning paradigm and immobility time in the forced swimming test. Firing rates of VTA neurons were significantly decreased upon bath application of the novel compound, which was not observed under the presence of a selective TAAR1 antagonist. A significant decrease in medial prefrontal cortex 5-HT levels were also observed after administration of the compound. Translational experiments utilizing clinically validated methods showed the novel compound significantly reduced total REM sleep time and delayed gastric emptying, consistent with previously reported TAAR1 agonists. Discussion & Conclusions This current study demonstrates our novel dual agonist exerts potential antipsychotic, anxiolytic and antidepressant effects in multiple preclinical models. The translational potency of the compound was also shown in two clinically validated tests. Our findings suggest our novel compound has potential to treat psychotic symptoms and beyond in multiple disorders characterized by psychosis.