Article

The classical D1 dopamine receptor antagonist SCH23390 is a functional sigma-1 receptor allosteric modulator

Gu-fang Zhang1, Kai-lian Zhu1, Qi Li1, Yue Zhang2, John L. Waddington1,3, Xiang-dong Du4, Xue-chu Zhen1
1 Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
2 Suzhou Medical College, Soochow University, Suzhou 215123, China
3 School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
4 Department of Psychiatry, The Affiliated Guangji Hospital of Soochow University, Suzhou 215003, China
Correspondence to: Xiang-dong Du: xiangdong-du@163.com, Xue-chu Zhen: zhenxuechu@suda.edu.cn,
DOI: 10.1038/s41401-024-01256-1
Received: 19 October 2023
Accepted: 28 February 2024
Advance online: 11 April 2024

Abstract

SCH23390 is a widely used D1 dopamine receptor (D1R) antagonist that also elicits some D1R-independent effects. We previously found that the benzazepine, SKF83959, an analog of SCH23390, produces positive allosteric modulation of the Sigma-1 receptor (Sig1R). SCH23390 does not bind to the orthodoxic site of Sig1R but enhances the binding of 3H (+)-pentazocine to Sig1R. In this study, we investigated whether SCH23390 functions as an allosteric modulator of Sig1R. We detected increased Sig1R dissociation from binding immunoglobulin protein (BiP) and translocation of Sig1R to the plasma membrane in response to SCH23390 in transfected HEK293T and SH-SY5Y cells, respectively. Activation of Sig1R by SCH23390 was further confirmed by inhibition of GSK3β activity in a time- and dose-dependent manner; this effect was blocked by pretreatment with the Sig1R antagonist, BD1047, and by knockdown of Sig1R. SCH23390 also inhibited GSK3β in wild-type mice but not in Sig1R knockout mice. Finally, we showed that SCH23390 allosterically modulated the effect of the Sig1R agonist SKF10047 on inhibition of GSK3β. This positive allosteric effect of SCH23390 was further confirmed via promotion of neuronal protection afforded by SKF10047 in primary cortical neurons challenged with MPP+. These results provide the first evidence that SCH23390 elicits functional allosteric modulation of Sig1R. Our findings not only reveal novel pharmacological effects of SCH23390 but also indicate a potential mechanism for SCH23390-mediated D1R-independent effects. Therefore, attention should be paid to these Sig1R-mediated effects when explaining pharmacological responses to SCH23390.

Keywords: SCH23390; Sigma-1 receptor; pharmacological actions; allosteric modulation; GSK3β

Article Options

Download Citation

Cited times in Scopus