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

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

机构地区：[1]School of Pharmacy,Xuzhou Medical University,Xuzhou 221004,China [2]Institute of Pharmaceutical Research,Jiangsu Nhwa Pharmaceutical Co.,Ltd.&Jiangsu Key Laboratory of Central Nervous System Drug Research and Development,Xuzhou 221116,China [3]Department of Pharmacology,School of Pharmacy,Qingdao University Medical College,Qingdao 266073,China [4]Institute of Innovative Drug,Qingdao University,Qingdao 266021,China [5]Center for Brain Science and Brain-Inspired Intelligence,Guangdong-Hong Kong-Macao Greater Bay Area,Guangzhou 510515,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第3期1457-1466,共10页药学学报（英文版）

基　　金：supported by research grants from Science and Technology Program of Guangdong(2018B030334001,China);the Ministry of Science and Technology of China(2018ZX09711001004-006)awarded to Ke Wei Wang。

摘　　要：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(K_(i)=30.1±6.9 nmol/L)and M channels(IC_(50)=10.1±2.4μmol/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 immobility 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.

关 键 词：SERT 5-HT Kv7/KCNQ/M current D01 DEPRESSION COGNITION 

分 类 号：R969[医药卫生—药理学]