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

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, was found to possess selective sigma-1 receptor agonist profiles via 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, which mediates, at least to some extent, 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.