Ren Peng, Wang Jing-Ya, Chen Hong-Lei, Chang Hai-Xia, Zeng Zhi-Rui, Li Guang-Xiang, Ma Hui, Zhao Yong-Qi, Li Yun-Feng
Beijing Institute of Basic Medical Sciences, Beijing, China.
Graduate Collaborative Training Base of Academy of Military Medical Sciences, Hengyang Medical School, University of South China, Hengyang, China.
Eur J Pharmacol. 2023 May 5;946:175647. doi: 10.1016/j.ejphar.2023.175647. Epub 2023 Mar 8.
The most intriguing characteristic of the sigma-1 receptor is its ability to regulate multiple functional proteins directly via protein-protein interactions, giving the sigma-1 receptor the powerful ability to regulate several survival and metabolic functions in cells, fine tune neuronal excitability, and regulate the transmission of information within brain circuits. This characteristic makes sigma-1 receptors attractive candidates for the development of new drugs. Hypidone hydrochloride (YL-0919), a novel structured antidepressant candidate developed in our laboratory, possess a selective sigma-1 receptor agonist profile, as evidenced by molecular docking, radioligand receptor binding assays, and receptor functional experiments. In vivo studies have revealed that YL-0919 elicits a fast-onset antidepressant activity (within one week) that can be attenuated with pretreatment of the selective sigma-1 receptor antagonist, BD-1047. Taken together, the findings of the current study suggest that YL-0919 activates the sigma-1 receptor to partially mediate the rapid onset antidepressant effects of YL-0919. Thus, YL-0919 is a promising candidate as a fast-onset antidepressant that targets the sigma-1 receptor.
σ-1受体最引人关注的特性是其能够通过蛋白质-蛋白质相互作用直接调节多种功能蛋白，这赋予了σ-1受体强大的能力来调节细胞中的多种生存和代谢功能、微调神经元兴奋性以及调节脑回路内的信息传递。这一特性使σ-1受体成为开发新药的有吸引力的候选对象。盐酸海皮酮（YL-0919）是我们实验室开发的一种新型结构的抗抑郁候选药物，具有选择性σ-1受体激动剂特征，分子对接、放射性配体受体结合试验和受体功能实验均证明了这一点。体内研究表明，YL-0919能引发快速起效的抗抑郁活性（在一周内），而选择性σ-1受体拮抗剂BD-1047预处理可减弱这种活性。综上所述，当前研究结果表明，YL-0919激活σ-1受体以部分介导其快速起效的抗抑郁作用。因此，YL-0919作为一种靶向σ-1受体的快速起效抗抑郁药是一个有前景的候选药物。
