Antipsychotic effect of the high-affinity sigma-1/2 receptor compound B1F
- 1Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China
- 2Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215123, China
- 3School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
Abstract
Current antipsychotics provide limited benefit for the negative and cognitive symptoms of schizophrenia, highlighting the need for novel treatments. We evaluated B1F, a newly identified high-affinity Sigma-1/2 receptor (Sigma-1/2 R) compound. We found that B1F attenuated MK-801-induced hyperlocomotion and reversed deficits in prepulse inhibition. B1F also improved chronic MK-801-induced impairments in social interaction and cognitive function. Pharmacological blockade and genetic deletion of Sigma-1R attenuated, but did not abolish, the effects of B1F on schizophrenia-like behaviors, suggesting that, in addition to Sigma-1R, other components, probably Sigma-2R, may also contribute to the drug's actions. Importantly, unlike the classical antipsychotic drugs, B1F did not induce extrapyramidal symptoms (EPS) at therapeutic doses. Finally, we found that B1F treatment inhibited glycogen synthase kinase 3β and activated cAMP response element-binding protein, thereby promoting brain-derived neurotrophic factor production while reducing endoplasmic reticulum stress. These findings provide proof-of-concept evidence that B1F's antipsychotic-like effects are largely Sigma-1R-dependent, with a Sigma-1R-independent component whose nature remains to be defined. B1F was effective against schizophrenia-like impairments without inducing EPS and may be a promising candidate against schizophrenia.
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BibTeX
@article{ma2026antipsychotic,
title = {{Antipsychotic effect of the high-affinity sigma-1/2 receptor compound B1F}},
author = {Zhixue Ma and Libin Wen and Zhifeng Shi and Yongjun Gao and Yuan-An Chen and Gufang Zhang and Jiaojiao Chen and Guangying Li and Huicui Yang and John L. Waddington and Na Ye and Xuechu Zhen},
journal = {Neurotherapeutics},
year = {2026},
month = oct,
doi = {10.1016/j.neurot.2026.e01105},
url = {https://doi.org/10.1016/j.neurot.2026.e01105},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Antipsychotic effect of the high-affinity sigma-1/2 receptor compound B1F
AU - Zhixue Ma
AU - Libin Wen
AU - Zhifeng Shi
AU - Yongjun Gao
AU - Yuan-An Chen
AU - Gufang Zhang
AU - Jiaojiao Chen
AU - Guangying Li
AU - Huicui Yang
AU - John L. Waddington
AU - Na Ye
AU - Xuechu Zhen
PY - 2026
DA - 2026/10/26
JO - Neurotherapeutics
DO - 10.1016/j.neurot.2026.e01105
UR - https://doi.org/10.1016/j.neurot.2026.e01105
AB - Current antipsychotics provide limited benefit for the negative and cognitive symptoms of schizophrenia, highlighting the need for novel treatments. We evaluated B1F, a newly identified high-affinity Sigma-1/2 receptor (Sigma-1/2 R) compound. We found that B1F attenuated MK-801-induced hyperlocomotion and reversed deficits in prepulse inhibition. B1F also improved chronic MK-801-induced impairments in social interaction and cognitive function. Pharmacological blockade and genetic deletion of Sigma-1R attenuated, but did not abolish, the effects of B1F on schizophrenia-like behaviors, suggesting that, in addition to Sigma-1R, other components, probably Sigma-2R, may also contribute to the drug's actions. Importantly, unlike the classical antipsychotic drugs, B1F did not induce extrapyramidal symptoms (EPS) at therapeutic doses. Finally, we found that B1F treatment inhibited glycogen synthase kinase 3β and activated cAMP response element-binding protein, thereby promoting brain-derived neurotrophic factor production while reducing endoplasmic reticulum stress. These findings provide proof-of-concept evidence that B1F's antipsychotic-like effects are largely Sigma-1R-dependent, with a Sigma-1R-independent component whose nature remains to be defined. B1F was effective against schizophrenia-like impairments without inducing EPS and may be a promising candidate against schizophrenia.
SN - 1933-7213
SN - 1878-7479
ER -