苏州大学Xue-chu Zhen等研究人员合作发现，经典的D1多巴胺受体拮抗剂SCH23390是一种功能性sigma-1受体异构调节剂。相关论文于2024年4月11日在线发表在《中国药理学报》杂志上。

研究人员表示，SCH23390是一种广泛使用的D1多巴胺受体（D₁R）拮抗剂，它也能产生一些与D₁R无关的作用。研究人员之前发现，SCH23390的类似物benzazepine SKF83959可对Sigma-1受体（Sig1R）产生异构调节作用。SCH23390不与Sig1R的正相位点结合，但能增强³H(+)-pentazocine与Sig1R的结合。

研究人员探讨了SCH23390是否具有Sig1R异构调节剂的功能。在转染的HEK293T细胞和SH-SY5Y细胞中，研究人员分别检测到Sig1R与结合免疫球蛋白（BiP）的解离增加以及Sig1R向质膜的转位。SCH23390对Sig1R的活化作用进一步通过抑制GSK3β活性得到证实，抑制作用具有时间和剂量依赖性；使用Sig1R拮抗剂BD1047进行预处理以及敲除Sig1R可阻断这种作用。SCH23390也能抑制野生型小鼠的GSK3β，但不能抑制Sig1R基因敲除小鼠的GSK3β。

最后，研究人员发现SCH23390异构调节了Sig1R激动剂SKF10047对GSK3β的抑制作用。通过促进SKF10047对受到MPP⁺挑战的原代皮质神经元的保护，进一步证实了SCH23390的这种积极的异构效应。

这些结果首次证明了SCH23390可对Sig1R进行功能性异构调节。这些研究结果不仅揭示了SCH23390的新药理作用，还指出了SCH23390介导的D₁R非依赖作用的潜在机制。因此，在解释对SCH23390的药理反应时，应注意这些由Sig1R介导的效应。

附：英文原文

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

Author: Zhang, Gu-fang, Zhu, Kai-lian, Li, Qi, Zhang, Yue, Waddington, John L., Du, Xiang-dong, Zhen, Xue-chu

Issue&Volume: 2024-04-11

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.

DOI: 10.1038/s41401-024-01256-1

Source: https://www.nature.com/articles/s41401-024-01256-1