2. Academic Validation
  3. Rational Design of the First Dual Agonist at Trace Amine-Associated Receptor 1 and 5-HT2C Receptors Based on Binding Pocket Similarity for the Treatment of Schizophrenia and Alzheimer's Disease-Related Psychosis

Rational Design of the First Dual Agonist at Trace Amine-Associated Receptor 1 and 5-HT2C Receptors Based on Binding Pocket Similarity for the Treatment of Schizophrenia and Alzheimer's Disease-Related Psychosis

  • J Med Chem. 2025 Apr 10;68(7):7082-7105. doi: 10.1021/acs.jmedchem.4c02291.
Jing Lu 1 2,  Pengfei Yu 2 3,  Yunjie Wang 1 2,  Yusen Dai 2,  Wenyan Wang 1 2,  Chunjiao Liu 2,  Lin Dong 2,  Hui Lei 2,  Yifei Yang 1 2,  Lin Wang 1 2,  Fangxia Zou 1 2,  Xuan Deng 1,  Bingsi Wang 2,  Shujuan Wei 2,  Mingxu Ma 1 2,  Hongbo Wang 1 2,  Liang Ye 2 4,  Jianzhao Zhang 1 2,  Jingwei Tian 1 2
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
  • 2 State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China.
  • 3 School of Pharmacy, Binzhou Medical University, Yantai 256603, China.
  • 4 School of Public Health, Binzhou Medical University, Yantai 256603, China.
PMID: 40159850 DOI: 10.1021/acs.jmedchem.4c02291
Abstract

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-HT2CR 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-HT2CR 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.

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