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

Abstract

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.

Protein Metabolism Changes and Alterations in Behavior of Trace Amine-Associated Receptor 1 Knockout Mice Fed a High-Fructose Diet

“…Furthermore, the AKT/GSK3 signaling pathway (not associated with the G protein-mediated D2 dopamine receptor signaling) was selectively activated, which is associated with the phosphorylation of AKT and GSK3β [ 21 ]. TAAR1 is being studied as a potential therapeutic target in the treatment of various mental disorders, such as schizophrenia [ 2 , 27 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT1A receptor agonist activity, currently being tested in phase III clinical development, with very promising results from the phase II trials, which led to the FDA designation as a breakthrough therapy for the treatment of schizophrenia [ 26 , 27 , 28 , 29 , 30 , 40 , 47 , 48 , 49 , 50 , 51 , 52 ].…”