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

作者机构：School of PharmacyXuzhou Medical UniversityXuzhou 221004China Institute of Pharmaceutical ResearchJiangsu Nhwa Pharmaceutical Co.Ltd.&Jiangsu Key Laboratory of Central Nervous System Drug Research and DevelopmentXuzhou 221116China Department of PharmacologySchool of PharmacyQingdao University Medical CollegeQingdao 266073China Institute of Innovative DrugQingdao UniversityQingdao 266021China Center for Brain Science and Brain-Inspired IntelligenceGuangdong-Hong Kong-Macao Greater Bay AreaGuangzhou 510515China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2024年第14卷第3期

页      面：1457-1466页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

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 

主　　题：SERT 5-HT Kv7/KCNQ/M current D01 Depression Cognition 

摘      要：Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving *** 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 *** 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 ***,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 ***,D01 reverses the long-term potentiation(LTP)inhibition induced by *** 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.