Neuropharmacological and antidepressant-like effects of ZY-1408: A novel serotonin/norepinephrine reuptake inhibitor and serotonin receptor 2C antagonist
Neuropharmacological and antidepressant-like effects of ZY-1408: A novel serotonin/norepinephrine reuptake inhibitor and serotonin receptor 2C antagonist
复制标题
ZY-1408的神经药理学和抗抑郁样作用：一种新型5-羟色胺/去甲肾上腺素再摄取抑制剂和5-羟色胺受体2C拮抗剂
DOI：
10.1016/j.neuropharm.2020.108376
复制
发表时间：
2021-01-01
影响因子：
4.7
通讯作者：
Jin, Zengliang
中科院分区：
文献类型：
--
作者：
Gao, Nana;Tiliwaerde, Murezati;Jin, Zengliang
抑郁症是一种常见的精神疾病，也是导致残疾的主要原因。目前大多数抗抑郁药都有明显的局限性，特别是起效延迟和有效率低。因此，仍然需要比现有标准更有效或耐受性更好的抗抑郁药。我们先前鉴定ZY-1408是一种具有新颖化学结构和潜在的抗类阿片活性的药物。具体而言，ZY-1408是一种新型5-羟色胺2C（5-HT 2C）受体拮抗剂和5-羟色胺/去甲肾上腺素（5-HT/NE）再摄取抑制剂。在这项研究中，我们进一步研究了ZY-1408的抗抑郁样疗效，使用体外和体内行为测试。ZY-1408具有5-HT_2C受体拮抗剂和5-HT/NE再摄取抑制剂的作用。同时，ZY-1408在大鼠（通过强迫游泳试验）和小鼠（通过悬尾试验）中以剂量依赖性方式降低体内不动性。行为测试结果似乎不是自发活动刺激的结果。在慢性应激大鼠中，ZY-1408重复治疗显著逆转了抑郁样行为，包括减少蔗糖偏好、减少运动活动和延长开始进食的时间。此外，在体内微透析表明，ZY-1408的管理显着增加细胞外5-HT和NE在自由活动的大鼠海马的浓度。因此，ZY-1408是一种有效的口服活性5-HT 2C受体拮抗剂和5-HT/NE再摄取抑制剂，在啮齿动物中具有抗抑郁样活性。
Depression is a common mental illness and leading cause of disability. Most current antidepressants are associated with significant limitations, and in particular, a delayed onset and low rate of efficacy. Consequently, there remains an ongoing need for antidepressants that are either more effective or better tolerated than existing standards. We previously identified ZY-1408 as a drug with a novel chemical structure and potential anti-depressant-like activity. Specifically, ZY-1408 is a novel serotonin 2C (5-HT2C) receptor antagonist and serotonin/norepinephrine (5-HT/NE) reuptake inhibitor. In this study, we further investigated the antidepressant-like efficacy of ZY-1408 using in vitro and in vivo behavioral tests. ZY-1408 showed 5-HT2C receptor antagonist and 5-HT/NE reuptake inhibitor properties in vitro. Meanwhile, ZY-1408 decreased immobility in vivo in a dose-dependent manner in rats (via the forced-swim test) and mice (via the tail-suspension test). The behavioral test results do not appear to result from stimulation of locomotor activity. In chronically stressed rats, repeated ZY-1408 treatment significantly reversed depressive-like behavior, including reduced sucrose preference, decreased locomotor activity, and prolonged time to begin eating. Furthermore, in vivo microdialysis showed that administration of ZY-1408 significantly increased extracellular concentrations of 5-HT and NE in the hippocampus of freely moving rats. Thus, ZY-1408 is a potent and orally active 5-HT2C receptor antagonist and 5-HT/NE reuptake inhibitor with antidepressant-like activity in rodents.