首页|A novel dual serotonin transporter and M-channel inhibitor D01 for antidepression and cognitive improvement

A novel dual serotonin transporter and M-channel inhibitor D01 for antidepression and cognitive improvement

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Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving cognition.In this study,we report a novel dual serotonin transporter and voltage-gated potassium Kv7/KCNQ/M-channel inhibitor D01(a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative)that exhibits both anti-depression effects and improvements in cognition.D01 inhibits serotonin transporters(Ki=30.1±6.9 nmol/L)and M channels(IC50=10.1±2.4 μmol/L).D01 also reduces the immobility duration in the mouse FST and TST assays in a dose-dependent manner without a stimulatory effect on locomotion.Intragastric administrations of D01(20 and 40 mg/kg)can significantly shorten the immo-bility time in a mouse model of chronic restraint stress(CRS)-induced depression-like behavior.Additionally,D01 dose-dependently improves the cognitive deficit induced by CRS in Morris water maze test and increases the exploration time with novel objects in normal or scopolamine-induced cognitive deficits in mice,but not fluoxetine.Furthermore,D01 reverses the long-term potentiation(LTP)inhibition induced by scopolamine.Taken together,our findings demonstrate that D01,a dual-target serotonin reuptake and M channel inhibitor,is highly effective in the treatment-resistant depression and cognitive deficits,thus holding potential for development as therapy of depression with cognitive deficits.

SERT5-HTKv7/KCNQ/M currentD01DepressionCognition

Yaqin Wei、Xiangqing Xu、Qiang Guo、Song Zhao、Yinli Qiu、Dongli Wang、Wenwen Yu、Yani Liu、KeWei Wang

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School of Pharmacy,Xuzhou Medical University,Xuzhou 221004,China

Institute of Pharmaceutical Research,Jiangsu Nhwa Pharmaceutical Co.,Ltd.& Jiangsu Key Laboratory of Central Nervous System Drug Research and Development,Xuzhou 221116,China

Department of Pharmacology,School of Pharmacy,Qingdao University Medical College,Qingdao 266073,China

Institute of Innovative Drug,Qingdao University,Qingdao 266021,China

Center for Brain Science and Brain-Inspired Intelligence,Guangdong-Hong Kong-Macao Greater Bay Area,Guangzhou 510515,China

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Science and Technology Program of Guangdong科技部项目

2018B0303340012018ZX09711001-004-006

2024

10.1016/j.apsb.2023.11.024

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(3)
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