Rational Design of the First Dual Agonist at Trace Amine-Associated Receptor 1 and 5-HT 2C Receptors Based on Binding Pocket Similarity for the Treatment of Schizophrenia and Alzheimer’s Disease-Related Psychosis

作者：Jing Lu, Pengfei Yu, Yunjie Wang, Yusen Dai, Wenyan Wang, Chunjiao Liu, Lin Dong, Hui Lei, Yifei Yang, Lin Wang, Fangxia Zou, Xuan Deng, Bingsi Wang, Shujuan Wei, Mingxu Ma, Hongbo Wang, Liang Ye, Jianzhao Zhang, Jingwei Tian · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.4c02291 · 被引用次数：6 · 研究领域：Receptor Mechanisms and Signaling、Neuroscience and Neuropharmacology Research、Pharmacological Receptor Mechanisms and Effects

The clinical-stage agonists for trace amine-associated receptor 1 (TAAR1) show insufficient clinical efficacy, requiring the design of new compounds beyond the TAAR1 receptor alone. Here, we provide evidence for the feasibility of designing TAAR1/5-HT 2C R dual agonists based on structural basis of these two targets and similarities of their agonists. Three series of novel agonists were discovered, leading to a potent compound named 21b . 21b exhibits submicromolar potency on both TAAR1 and 5-HT 2C R targets with high specificity confirmed by site-directed mutagenesis. Preclinical proof-of-concept studies showed that 21b was highly efficacious against the positive and negative symptoms of schizophrenia in mice models. 21b also alleviated cognitive deficits and psychoactive symptoms in Alzheimer’s disease (AD) model mice. Four week repeated dosing of 21b is exceptionally well tolerated in rats and beagle dogs without hyperglycemia commonly seen with antipsychotics. Thus, the favorable druggability of compound 21b warrants further clinical development for the treatment of schizophrenia and AD-related psychosis.