Sigma-1 receptor agonist properties that mediate the fast-onset antidepressant effect of hypidone hydrochloride (YL-0919)

• Published in: European journal of pharmacology 2023-05, Vol.946, p.175647-175647, Article 175647
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Antidepressant; Antidepressive Agents - metabolism; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Fast-onset; Major depression; Molecular docking; Molecular Docking Simulation; Receptors, sigma - metabolism; Sigma-1 Receptor; YL-0919; σ-1 receptors
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2023.175647

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. •YL-0919 is a novel σ-1 receptor agonist.•σ-1 receptor is involved in the fast-onset antidepressant effect of YL-0919.•Targeting the σ-1 receptor may contribute to the discovery of fast-onset antidepressants.