关键词: hypidone hydrochloride（YL-0919）, 5-HT6 receptor agonist, cognitionenhancing, antidepressant, anxiolytic, cAMP

Abstract: Hypidone hydrochloride (YL-0919), the 5-HT1A/6 agonists and 5-HT reuptake inhibitor, is a novel potent antidepressant with original chemical structure. Previous studies confirmed that YL-0919 has significant antidepressant- and anxiolytic-like effects. Compared with first-line antidepressants, YL-0919 possesses rapid-onset and cognition-enhancing advantages without causing sexual disorders. Recently, it has been found that it has high affinity with 5-HT6 receptor.  Objective: To study the target characteristics of YL-0919 to 5-HT6 receptors, and to explore the relationship between the 5-HT6 receptor and the cognition-enhancing, antidepressant/anxiolytic-like effects of YL-0919 and targeting mechanisms. Methods: The radioligand binding inhibition test and [35S]-GTPγS binding assay were used to evaluate the binding affinity of YL-0919 to 5-HT6 receptor in rat striatum, transient CHO cell line and stable Hela cell lines. Novel object recognition (NOR), Morris water maze (MWM) and step-down test (SD) were used to evaluate the cognition-enhancing activity of YL-0919, and the selective 5-HT6 receptor antagonist SB271046 was used to evaluate the relationship between behavioral improvement caused by YL-0919 and 5-HT6 receptor activation. To study the 5-HT6 receptor related mechanisms of YL-0919, the competitive immunofluorescence assay were used to examine the cAMP level in h5-HT6 receptor-expressed in the Hela cells Results: (1) Radioligand competitive binding experiments showed that YL-0919 had high binding affinity with 5-HT6 receptors in the rat striatum, the CHO cells transiently expressed the h5-HT6 receptor and the Hela cells stably expressed the h5-HT6 receptor, with Ki of 10.72, 14.76 and 28.12nM respectively; [35S]-GTPγS showed full agonist characteristics of YL-0919 in striatum and cells, with EC50 of 71.23, 64.73 and 52.92nM respectively, and the maximum efficiency (Emax) reached 100% which is the same to the 5-HT6 receptor agonist WAY208466, suggesting that YL-0919 is a full 5-HT6 receptor agonist. (2) Cognitive-related behavioral tests showed that subchronic oral administration of YL-0919 (1.25-2.5 mg•kg-1) could significantly increase the recognition index in NOR, the entries and duration in the target quadrant, the entries crossing the platform in WMW, shortened the first time crossing the platform in MWM and the step-down latency in SD, suggesting the cognition-enhancing effects of YL-0919; compared with Vilazodone, the partial agonist of 5-HT1A receptor and 5-HT reuptake inhibitor, which of no such functions; Further study showed that 5-HT6 receptor antagonist SB271046(10mg•kg-1) completely blocked the cognition-enhancing effects of YL-0919 without affecting the cognitive activity itself, suggesting that 5-HT6 receptor activation might be its underlying mechanisms; (3) Mechanism study found that YL-0919 could significantly increase cAMP levels in the Hela cells stably-expressed the h5-HT6 receptor, which could be dose-dependent blocked by SB271046. Conclusion: YL-0919 is a full agonist of 5-HT6 receptor. YL-0919 showed significant cognition-enhancing effects in various kinds of animal models, and its underlying important mechanism might be activating 5-HT6 receptor. In addition, enhancing downstream cAMP-CREB signaling pathway of 5-HT6 receptor might at least partially mediate the above process. Moreover, 5-HT6 receptor activation might also be one of the mechanisms of antidepressant- and anxiolytic-like effects of YL-0919. In conclusion, this study confirmed the 5-HT6 receptor-related mechanisms of YL-0919, the 1.1 types of antidepressants, laying the experimental foundation for developing novel antidepressants with cognition-enhancing effects.