5-HT6 receptor agonist and memory-enhancing properties of hypidone hydrochloride (YL-0919), a novel 5-HT1A receptor partial agonist and SSRI
5-HT6 receptor agonist and memory-enhancing properties of hypidone hydrochloride (YL-0919), a novel 5-HT1A receptor partial agonist and SSRI
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盐酸乙二酮 (YL-0919) 的 5-HT6 受体激动剂和记忆增强特性，一种新型 5-HT1A 受体部分激动剂和 SSRI
DOI：
10.1016/j.neuropharm.2018.05.027
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发表时间：
2018-08-01
影响因子：
4.7
通讯作者：
Li, Yun-Feng
中科院分区：
文献类型：
--
作者：
Chen, Xiao-fei;Jin, Zeng-liang;Li, Yun-Feng
目前大多数抗抑郁药缺乏促认知作用，甚至作为副作用损害认知，并且很少有有效的精神药理学选择可以改善抑郁症的认知功能障碍。本课题组前期研究发现，新型5-HT 1A受体部分激动剂盐酸噻哌酮（YL-0919）具有抗抑郁和抗焦虑作用。在此，进一步的研究发现，YL-0919，而不是维拉唑酮（5-HT 1A受体部分激动剂和SSRI），在Morris水迷宫，物体识别测试和跳台被动回避任务中表现出显著的记忆增强作用。由于5-HT 6受体已成为改善认知的有趣药物靶标，因此我们使用放射性配体结合测定[S-35]-GTP γ S结合和cAMP刺激测定研究了YL-0919的靶标特征。发现YL-0919作为5-HT 6受体的高效完全激动剂起作用。最后，我们观察到YL-0919的记忆增强活性在以不改变认知的剂量与SB 271046（一种选择性5-HT 6受体拮抗剂）共同给药后完全逆转。总之，本研究的结果表明YL-0919具有明显的记忆增强作用，这可能至少部分由5-HT 6受体激活介导。(C)2018爱思唯尔有限公司版权所有。
Most current antidepressants are lacking a pro-cognition effect or even impair cognition as a side effect, and there are few effective psychopharmacological options that improve cognitive dysfunction in depression. Our previous studies revealed that hypidone hydrochloride (YL-0919), a novel 5-HT1A receptor partial agonist and SSRI, has antidepressant- and anxiolytic-like effects. Here, further studies found that YL-0919, but not vilazodone (a 5-HT1A receptor partial agonist and SSRI), exerted a significant memory-enhancing effect in the Morris water maze, object recognition test and step-down passive avoidance task. Because the 5-HT6 receptor has emerged as an interesting drug target to improve cognition, we investigated the target profile of YL-0919 using radioligand binding assays [S-35]-GTP gamma S binding and cAMP stimulation assays. YL-0919 was found to act as a highly effective, full agonist of 5-HT6 receptors. Finally, we observed that the memory-enhancing activities of YL-0919 were completely reversed after co-administration of SB271046 (a selective 5-HT6 receptor antagonist) at a dose that does not alter cognition. In summary, the findings of the current study suggest that YL-0919 has clear memory-enhancing effects, which might be at least partially mediated by 5-HT6 receptor activation. (C) 2018 Elsevier Ltd. All rights reserved.