Discovery and proof-of-concept study of a novel highly selective sigma-1 receptor agonist for antipsychotic drug development.

Wanyu TANG; Zhixue MA; Bang LI; Zhexiang YU; Xiaobao ZHAO; Huicui YANG; Jian HU; Sheng TIAN; Linghan GU; Jiaojiao CHEN; Xing ZOU; Qi WANG; Fan CHEN; Guangying LI; Chaonan ZHENG; Shuliu GAO; Wenjing LIU; Yue LI; Wenhua ZHENG; Mingmei WANG; Na YE; Xuechu ZHEN

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Discovery and proof-of-concept study of a novel highly selective sigma-1 receptor agonist for antipsychotic drug development.

Author: Wanyu TANG ¹ ; Zhixue MA ¹ ; Bang LI ¹ ; Zhexiang YU ¹ ; Xiaobao ZHAO ¹ ; Huicui YANG ¹ ; Jian HU ¹ ; Sheng TIAN ¹ ; Linghan GU ¹ ; Jiaojiao CHEN ¹ ; Xing ZOU ¹ ; Qi WANG ¹ ; Fan CHEN ¹ ; Guangying LI ¹ ; Chaonan ZHENG ¹ ; Shuliu GAO ¹ ; Wenjing LIU ¹ ; Yue LI ¹ ; Wenhua ZHENG ² ; Mingmei WANG ³ ; Na YE ¹ ; Xuechu ZHEN ¹
Author Information

1. Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
2. Center of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR 999078, China.
3. College of Biology & Food Sciences, Suzhou University of Technology, Suzhou 215500, China.
Publication Type:Journal Article
Keywords: Agonist; Antipsychotic; Central nervous system; Drug development; Oxime ether; Schizophrenia; Sigma-1 receptor; Structure-based design
From: Acta Pharmaceutica Sinica B 2025;15(10):5346-5365
CountryChina
Language:English
Abstract: Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.