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.

SUBMITTER: Krasavin M 

PROVIDER: S-EPMC9569940 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature