SKF83959 is a novel triple reuptake inhibitor that elicits anti-depressant activity  

作　　者：Xing Fang Lin Guo Jia Jia Guo-zhang Jin Bin Zhao Yong-yong Zheng Jian-qi Li Ao Zhang Xue-chu Zhen 

机构地区：[1]Department of Pharmacology II & Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2]Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China [3]Department of Neurology, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China [4]Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, China

出　　处：《Acta Pharmacologica Sinica》2013年第9期1149-1155,共7页中国药理学报（英文版）

基　　金：This work was financially supported by grants obtained from the National Natural Science Foundation of China （81130023, 81100918, and 81271214）; National Basic Research Plan （973） of the Ministry of Science and Technology of China （2009CB522000 and 2011CB5C4403）; We also appreciate the support provided by the Priority Academic Program Development of Jiangsu Higher Education Institutes （PAPD） and a grant obtained from the Jiangsu Science and Technology Commission （BY2011131）.

摘　　要：Aim： SKF83959 （3-methyl-6-chloro-7,8-hydroxy-1-（3-methylphenyl）-2,3,4,5-tetrahydro-1H-3-benzazepine） is an atypical dopamine receptor-1 （D1 receptor） agonist, which exhibits many D1 receptor-independent effects. In the present work, we examined the effects of SKF83959 on monoaminergic transporters in vitro and its anti-depressant activity in vivo.Methods： Human serotonin transporter （SERT）, norepinephrine transporters （NET） or dopamine transporters （DAT） were stably expressed in CHO cells. The uptake kinetics of SERT, NET, and DAT were examined using [3H]-serotonin, [3H]-norepinephrine or [3H]-dopamine, respectively. A triple reuptake inhibitor DOV21947 was used as the positive control. Tail suspension test and forced swimming test were conducted in mice. SKF83959 or DOV21947 （2-8 mg/kg） were intraperitoneally injected 30 min before the tests.Results： SKF83959 was a competitive inhibitor of SERT （Ki=1.43±0.45 μmol/L）, but a noncompetitive inhibitor of NET （Ki=0.60±0.07 μmol/L） and DAT （Ki=9.01±0.80 μmol/L）. In contrast, DOV21947 was a competitive inhibitor of SERT （Ki=0.89±0.24 μmol/L） and DAT （Ki=1.47±0.31 μmol/L） and a noncompetitive inhibitor of NET （Ki=0.18±0.04 μmol/L）. In mice, both SKF83959 and DOV21947 elicited anti-depressant activity in a dose-dependent manner.Conclusion： SKF83959 functions as a novel triple reuptake inhibitor in vitro and exerts anti-depressant effects in vivo.Aim： SKF83959 （3-methyl-6-chloro-7,8-hydroxy-1-（3-methylphenyl）-2,3,4,5-tetrahydro-1H-3-benzazepine） is an atypical dopamine receptor-1 （D1 receptor） agonist, which exhibits many D1 receptor-independent effects. In the present work, we examined the effects of SKF83959 on monoaminergic transporters in vitro and its anti-depressant activity in vivo.Methods： Human serotonin transporter （SERT）, norepinephrine transporters （NET） or dopamine transporters （DAT） were stably expressed in CHO cells. The uptake kinetics of SERT, NET, and DAT were examined using [3H]-serotonin, [3H]-norepinephrine or [3H]-dopamine, respectively. A triple reuptake inhibitor DOV21947 was used as the positive control. Tail suspension test and forced swimming test were conducted in mice. SKF83959 or DOV21947 （2-8 mg/kg） were intraperitoneally injected 30 min before the tests.Results： SKF83959 was a competitive inhibitor of SERT （Ki=1.43±0.45 μmol/L）, but a noncompetitive inhibitor of NET （Ki=0.60±0.07 μmol/L） and DAT （Ki=9.01±0.80 μmol/L）. In contrast, DOV21947 was a competitive inhibitor of SERT （Ki=0.89±0.24 μmol/L） and DAT （Ki=1.47±0.31 μmol/L） and a noncompetitive inhibitor of NET （Ki=0.18±0.04 μmol/L）. In mice, both SKF83959 and DOV21947 elicited anti-depressant activity in a dose-dependent manner.Conclusion： SKF83959 functions as a novel triple reuptake inhibitor in vitro and exerts anti-depressant effects in vivo.

关 键 词：SKF83959 monoamine transporter SEROTONIN NOREPINEPHRINE DOPAMINE DEPRESSION DOV21947 

分 类 号：Q422[生物学—神经生物学] TQ460.6[生物学—生理学]