TY - JOUR

T1 - 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

AU - Krasavin, Mikhail

AU - Peshkov, Anatoly A.

AU - Lukin, Alexey

AU - Komarova, Kristina

AU - Vinogradova, Lyubov

AU - Smirnova, Daria

AU - Kanov, Evgeny V.

AU - Kuvarzin, Savelii R.

AU - Murtazina, Ramilya Z.

AU - Efimova, Evgeniya V.

AU - Gureev, Maxim

AU - Onokhin, Kirill

AU - Zakharov, Konstantin

AU - Gainetdinov, Raul R.

N1 - Publisher Copyright: © 2022 by the authors.

PY - 2022/9/30

Y1 - 2022/9/30

N2 - 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.

AB - 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.

KW - agonists

KW - antipsychotic

KW - biogenic amine mimetics

KW - dopamine transporter knockout rats

KW - hyperlocomotion

KW - molecular modeling

KW - psychotic disorders

KW - schizophrenia

KW - trace amine-associated receptor 1

KW - Dopamine

KW - Rats

KW - Animals

KW - Receptors, G-Protein-Coupled/metabolism

KW - Piperidines/pharmacology

KW - Psychotic Disorders

KW - Dopamine Plasma Membrane Transport Proteins

UR - http://www.scopus.com/inward/record.url?scp=85139850449&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/a3e2ac6b-78a2-30ed-a0a7-32bcf1ae37bf/

U2 - 10.3390/ijms231911579

DO - 10.3390/ijms231911579

M3 - Article

C2 - 36232878

AN - SCOPUS:85139850449

VL - 23

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 19

M1 - 11579

ER -