2. Academic Validation
  3. Synthesis and evaluation of novel 5-HT2A receptor inverse agonist with excellent in vivo antipsychotic efficacy and superior tissue distribution for treatment of Parkinson's disease psychosis

Synthesis and evaluation of novel 5-HT2A receptor inverse agonist with excellent in vivo antipsychotic efficacy and superior tissue distribution for treatment of Parkinson's disease psychosis

  • Eur J Med Chem. 2025 Nov 15:298:118044. doi: 10.1016/j.ejmech.2025.118044.
Mingxu Ma 1,  Guangying Du 1,  Wenyan Wang 1,  Yusen Dai 2,  Hengwei Xu 1,  Yingjie Wei 2,  Huijie Yang 2,  Xiaoyin Zhu 1,  Min Zhao 2,  Yonglin Gao 3,  Jianzhao Zhang 1,  Liang Ye 4,  Jingwei Tian 5
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; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, China.
  • 2 State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, China.
  • 3 State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, China; College of Life Sciences, Yantai University, Yantai, 264005, China.
  • 4 State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, China; School of Public Health and Management, Binzhou Medical University, Yantai, 256603, China. Electronic address: project0088@hotmail.com.
  • 5 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; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, China. Electronic address: Tianjingwei618@163.com.
PMID: 40784305 DOI: 10.1016/j.ejmech.2025.118044
Abstract

Pimavanserin is a 5-HT2A receptor inverse agonist as the first and only drug approved for the treatment of Parkinson's disease psychosis (PDP), which has a black box warning regarding an increased risk of death in elderly patients with dementia-related psychosis and warning related to QTc interval prolongation. In this article, a total of 25 novel modulated pimavanserin derivatives were designed and synthesized. The optimal compound P25a exhibited better 5-HT2A receptor inverse agonist activity and lower hERG inhibition than that of pimavanserin. Molecular dynamics simulations also indicated that compound P25a had a more stable binding mode with the receptor. Moreover, compound P25a exhibited almost 2.2-fold AUClast increasement in in vivo pharmacokinetics study with higher exposure in brain and lower distribution in cardiac tissue. Compound P25a demonstrated higher functional activities in both DOI-induced head twitches model and MK801-induced hyperactivity model. In conclusion, the enhanced in vitro and in vivo efficacy profiles, minimal hERG inhibition, and superior tissue distribution, established compound P25a as a promising preclinical candidate for treatment of PDP that warranted further investigation.

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