Biological evaluation and in silico studies of novel compounds as potent TAAR1 agonists that could be used in schizophrenia treatment

Frontiers in Pharmacology

Pharmacology

Jianzhao Zhang¹  Yunjie Wang²  Jing Lu²  Zhaofeng Liu²  Yifei Yang²  Lin Wang²  Wenyan Wang²  Jingwei Tian²  Hongbo Wang²  Liang Ye³ 

[1]College of Life Sciences, Yantai University, Yantai, China

[2]Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China

[3]School of Public Health and Management, Binzhou Medical University, Yantai, China

关键词: trace amine-associated receptor 1;    anti-schizophrenia;    security;    molecular modeling;    biological evaluation;   

DOI  :  10.3389/fphar.2023.1161964

 received in 2023-02-09, accepted in 2023-04-05,  发布年份 2023

来源: Frontiers

【 摘 要 】

Introduction: Schizophrenia is a serious mental illness that requires effective treatment with minimal adverse effects. As preclinical and clinical research progresses, trace amine-associated receptor 1 (TAAR1) is becoming a potential new target for the treatment of schizophrenia.Methods: We used molecular docking and molecular dynamics (MD) simulations to discover TAAR1 agonists. The agonistic or inhibitory effects of compounds on TAAR1, 5-HT1A, 5-HT2A, and dopamine D2-like receptors were determined. We used an MK801-induced schizophrenia-like behavior model to assess the potential antipsychotic effects of compounds. We also performed a catalepsy assay to detect the adverse effects. To evaluate the druggability of the compounds, we conducted evaluations of permeability and transporter substrates, liver microsomal stability in vitro, human ether-à-go-go-related gene (hERG), pharmacokinetics, and tissue distribution.Results: We discovered two TAAR1 agonists: compounds 50A and 50B. The latter had high TAAR1 agonistic activity but no agonistic effect on dopamine D2-like receptors and demonstrated superior inhibition of MK801-induced schizophrenia-like behavior in mice. Interestingly, 50B had favorable druggability and the ability to penetrate the blood-brain barrier (BBB) without causing extrapyramidal symptoms (EPS), such as catalepsy in mice.Conclusion: These results demonstrate the potential beneficial role of TAAR1 agonists in the treatment of schizophrenia. The discovery of a structurally novel TAAR1 agonist (50B) may provide valuable assistance in the development of new treatments for schizophrenia.

【 授权许可】

Unknown   
Copyright © 2023 Wang, Liu, Lu, Wang, Wang, Yang, Wang, Ye, Zhang and Tian.