Medicinal chemistry advances of TAAR1 agonists: SAR, structural innovation, and mechanistic insights
Wenyu Zhang1, Wu Wu2, Jing Gao1
1Department of Pulmonary and Critical Care Medicine, Molecularly Targeted Research and Development Laboratory, Institute of Respiratory Health, Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
Abstract:
Trace amine-associated receptor 1 (TAAR1) is an important member of the trace amine receptor family that plays a crucial regulatory role in both the central and peripheral nervous systems. It is a promising therapeutic target for various diseases, especially psychiatric disorders. Importantly, TAAR1-targeted therapies generally exhibit favorable metabolic safety profiles and may alleviate negative and cognitive symptoms. Extensive research has demonstrated that selective TAAR1 ligands have significant pharmacological effects in preclinical models of psychiatric conditions. However, only SEP-363856 and ralmitaront have advanced into clinical trials for schizophrenia to date, highlighting the considerable opportunities that remain for the development of TAAR1-targeted therapeutics. This review provides a comprehensive overview of TAAR1's structure, biological functions, and its connection to human diseases. Additionally, it summarizes the design strategies, structure-activity relationships, and pharmacological properties of TAAR1 agonists, aiming to guide future drug development and clinical applications.
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