Abstract：
Inhibitors of dopamine transporters (DAT), norepinephrine transporters (NET) and serotonin transporters (SERT) are effective treatments for neuropsychiatric diseases. Dasotraline [(1R,4 S)- 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1-naphthalenamine, also known as SEP-225289) was evaluated for its inhibitory potency at DAT, NET and SERT using in vitro and in vivo assays. In vitro radiometric functional uptake studies showed preferential inhibition by dasotraline of hDAT (IC50 =3 nM) and hNET (IC50 =4 nM relative to hSERT(IC50 =15 nM). In mouse ex vivo occupancy studies, dasotraline demonstrated total plasma concentration-dependent occupancy at DAT, NET and SERT. Determination of the TO50 (50% transporter occupancy) were 32, 109 and 276 ng/ml, respectively. In SPECT imaging studies in baboons, dasotraline (0.2 mg/kg iv) displaced radiotracer binding to DAT by 87% but only 20% at NET and SERT. Rat microdialysis studies were performed in prefrontal cortex and striatum. Dasotraline produced sustained (>4 h) increases in dopamine and norepinephrine concentrations. Dasotraline was also more potent at increasing synaptic dopamine in the striatum, and norepinephrine in the prefrontal cortex than serotonin in these regions. In summary, dasotraline preferentially inhibits DAT and NET relative to SERT. Together, the occupancy and neurochemical profile of dasotraline provide a mechanistic basis for the treatment of diseases that have an underlying causality involving dopamine and norepinephrine dysfunction.
摘要：
多巴胺转运蛋白（DAT）抑制剂，去甲肾上腺素转运体（NET）和5-羟色胺转运体（SERT）是治疗神经精神疾病的有效方法。Dasotraline[(1R，4S)-4-(3,4-二氯苯基)-1,2,3,4-四氢-1-萘胺,也称为SEP-225289)对其在DAT的抑制效力进行了评估，NET和SERT使用体外和体内测定。体外放射性功能摄取研究显示达索曲林优先抑制hDAT(IC50=3nM)和hNET(IC50=4nM,相对于hSERT(IC50=15nM)。在小鼠离体占据研究中，达索曲林在DAT表现出总血浆浓度依赖性占有率，NET和SERT。测定的TO50（50％转运蛋白占有率）分别为32、109和276ng/ml，分别。在狒狒的SPECT成像研究中，达索曲林（0.2mg/kgiv）将与DAT结合的放射性示踪剂置换了87％，但在NET和SERT时仅置换了20％。在前额叶皮质和纹状体中进行了大鼠微透析研究。达索曲林产生持续（>4小时）的多巴胺和去甲肾上腺素浓度增加。Dasotraline在增加纹状体中的突触多巴胺方面也更有效，和去甲肾上腺素在前额叶皮质比5-羟色胺在这些区域。总之,达索曲林相对于SERT优先抑制DAT和NET。一起,dasotraline的占用和神经化学特征为治疗具有涉及多巴胺和去甲肾上腺素功能障碍的潜在因果关系的疾病提供了机制基础。
