Rational Design of the First Dual Agonist at Trace Amine-Associated Receptor 1 and 5-HT<sub>2C</sub> Receptors Based on Binding Pocket Similarity for the Treatment of Schizophrenia and Alzheimer’s Disease-Related Psychosis
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<sub>2C</sub>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 <b>21b</b>. <b>21b</b> exhibits submicromolar potency on both TAAR1 and 5-HT<sub>2C</sub>R targets with high specificity confirmed by site-directed mutagenesis. Preclinical proof-of-concept studies showed that <b>21b</b> was highly efficacious against the positive and negative symptoms of schizophrenia in mice models. <b>21b</b> also alleviated cognitive deficits and psychoactive symptoms in Alzheimer's disease (AD) model mice. Four week repeated dosing of <b>21b</b> is exceptionally well tolerated in rats and beagle dogs without hyperglycemia commonly seen with antipsychotics. Thus, the favorable druggability of compound <b>21b</b> warrants further clinical development for the treatment of schizophrenia and AD-related psychosis.
Authors
- Wenyan Wang (ORCID: https://orcid.org/0000-0003-0589-654X)
- Shujuan Wei (ORCID: https://orcid.org/0000-0003-4677-0572)
- Bingsi Wang
- Chunjiao Liu (ORCID: https://orcid.org/0000-0003-3913-1887)
- Jingwei Tian (ORCID: https://orcid.org/0000-0001-8029-0236)
- Fangxia Zou (ORCID: https://orcid.org/0000-0001-9356-5614)
- Yusen Dai
- Jianzhao Zhang (ORCID: https://orcid.org/0000-0003-0277-7166)
- Xuan Deng
- Liang Ye (ORCID: https://orcid.org/0000-0001-9099-363X)
- Hongbo Wang (ORCID: https://orcid.org/0000-0001-8530-2339)
- Lin Wang (ORCID: https://orcid.org/0000-0001-5716-6587)
- Hui Lei (ORCID: https://orcid.org/0000-0002-9448-9673)
- Mingxu Ma
- Yunjie Wang (ORCID: https://orcid.org/0009-0009-1133-6718)
- Yifei Yang (ORCID: https://orcid.org/0000-0002-1507-7655)
- Jing Lu (ORCID: https://orcid.org/0000-0001-9195-7470)
- Lin Dong (ORCID: https://orcid.org/0000-0002-7207-9825)
- Pengfei Yu (ORCID: https://orcid.org/0000-0003-4702-2648)
Institutions
- Binzhou Medical University (CN)
- Shandong University of Aeronautics (CN)
- Yantai University (CN)
- Luye Pharma (China) (CN)
- Systèmes avancés de délivrance de principes actifs
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-31
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02291
- Citations
- 4
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Shandong Province
- Taishan Scholar Project of Shandong Province
- Yantai Science and Technology Bureau
- Taishan Industry Leading Talents