Department of Pharmacology II & Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Acta Pharmacol Sin. 2013 Sep;34(9):1149-55. doi: 10.1038/aps.2013.66. Epub 2013 Jul 29.
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.
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.
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.
SKF83959 functions as a novel triple reuptake inhibitor in vitro and exerts anti-depressant effects in vivo.
SKF83959（3-甲基-6-氯-7,8-羟基-1-（3-甲基苯基）-2,3,4,5-四氢-1H-3-苯并氮杂䓬）是一种非典型多巴胺受体-1（D1 受体）激动剂，具有许多 D1 受体非依赖性作用。本研究旨在体外观察 SKF83959 对单胺转运体的作用，并观察其体内抗抑郁活性。
人血清素转运体（SERT）、去甲肾上腺素转运体（NET）或多巴胺转运体（DAT）在 CHO 细胞中稳定表达。采用 [(3)H]-血清素、[(3)H]-去甲肾上腺素或 [(3)H]-多巴胺分别检测 SERT、NET 和 DAT 的摄取动力学。使用三重再摄取抑制剂 DOV21947 作为阳性对照。采用悬尾试验和强迫游泳试验检测 SKF83959 或 DOV21947（2-8 mg/kg）的抗抑郁活性。在试验前 30 min 腹腔注射 SKF83959 或 DOV21947。
SKF83959 是 SERT 的竞争性抑制剂（K(i)=1.43±0.45 μmol/L），但对 NET（K(i)=0.60±0.07 μmol/L）和 DAT（K(i)=9.01±0.80 μmol/L）的抑制是非竞争性的。相比之下，DOV21947 是 SERT（K(i)=0.89±0.24 μmol/L）和 DAT（K(i)=1.47±0.31 μmol/L）的竞争性抑制剂，NET（K(i)=0.18±0.04 μmol/L）的非竞争性抑制剂。在小鼠中，SKF83959 和 DOV21947 均呈剂量依赖性发挥抗抑郁作用。
SKF83959 是一种新型三重再摄取抑制剂，在体内具有抗抑郁作用。
