title: SKF83959 is a novel triple reuptake inhibitor that elicits anti-depressant activity.
abstract: OBJECTIVE
  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 [(3)H]-serotonin, [(3)H]-norepinephrine or [(3)H]-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 (K(i)=1.43±0.45 μmol/L), but a noncompetitive inhibitor of NET (K(i)=0.60±0.07 μmol/L) and DAT (K(i)=9.01±0.80 μmol/L). In contrast, DOV21947 was a competitive inhibitor of SERT (K(i)=0.89±0.24 μmol/L) and DAT (K(i)=1.47±0.31 μmol/L) and a noncompetitive inhibitor of NET (K(i)=0.18±0.04 μmol/L). In mice, both SKF83959 and DOV21947 elicited anti-depressant activity in a dose-dependent manner.
  
  
  CONCLUSIONS
  SKF83959 functions as a novel triple reuptake inhibitor in vitro and exerts anti-depressant effects in vivo.
authors.affiliation: Department of Pharmacology II & Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Fang
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.forename: Jia
authors.initials: J
authors.lastname: Jia
authors.forename: Guo-zhang
authors.initials: GZ
authors.lastname: Jin
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.forename: Yong-yong
authors.initials: YY
authors.lastname: Zheng
authors.forename: Jian-qi
authors.initials: JQ
authors.lastname: Li
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
authors.forename: Xue-chu
authors.initials: XC
authors.lastname: Zhen
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C080703:SK&F 83959
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