Russ H, Sonna J, Keppler K, Baunach S, Schömig E
Department of Pharmacology, University of Würzburg, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1993 Nov;348(5):458-65. doi: 10.1007/BF00173203.
The neurotransmitter noradrenaline is removed from the extracellular space by neuronal and extraneuronal transport mechanisms. In the past, further functional and biochemical characterisation of the corticosterone-sensitive extraneuronal transporter was hampered by the lack of highly potent inhibitors. Here we describe a new class of selective and highly potent inhibitors of the extraneuronal noradrenaline transporter. Clonal Caki-1 cells possess the human type of extraneuronal noradrenaline carrier. The effect of various steroids and steroid-like compounds on initial rates of specific 3H-noradrenaline transport in Caki-1 cells was investigated. None of these steroids had an inhibitory potency higher than that of corticosterone which hitherto was generally accepted as the most potent inhibitor of the extraneuronal noradrenaline transport. On the other hand, a variety of quinoline and isoquinoline derivatives interacted with the extraneuronal noradrenaline transporter. Several cationic quinolines that belong to the chemical class of the cyanine dyes turned out to be very potent inhibitors of 3H-noradrenaline transport in Caki-1 cells. The isocyanines, 1,1'-diisopropyl-2,4'-cyanine (disprocynium24) and 1-methyl-1'-isopropyl-2,4'-cyanine as well as the pseudoisocyanines 1,1'-diethyl-2,2'-cyanine (decynium22) and 1-isopropyl-1'-ethyl-2,2'-cyanine (iprecynium22) were most potent with IC50's of 14, 62, 16, and 18 nmol/l, respectively. The inhibitory potency on extraneuronal noradrenaline transport of 1-methyl-1'-isopropyl-2,4'-cyanine was determined also in isolated organs, namely the isolated incubated rabbit aorta and the isolated perfused rat heart.(ABSTRACT TRUNCATED AT 250 WORDS)
神经递质去甲肾上腺素通过神经元和非神经元转运机制从细胞外空间被清除。过去，由于缺乏高效抑制剂，对皮质酮敏感的非神经元转运体的进一步功能和生化特性研究受到阻碍。在此，我们描述了一类新型的非神经元去甲肾上腺素转运体的选择性高效抑制剂。克隆的Caki-1细胞具有人类类型的非神经元去甲肾上腺素载体。研究了各种类固醇和类固醇样化合物对Caki-1细胞中特异性3H-去甲肾上腺素转运初始速率的影响。这些类固醇中没有一种的抑制效力高于皮质酮，而皮质酮一直被普遍认为是最有效的非神经元去甲肾上腺素转运抑制剂。另一方面，多种喹啉和异喹啉衍生物与非神经元去甲肾上腺素转运体相互作用。几种属于花青染料化学类别的阳离子喹啉被证明是Caki-1细胞中3H-去甲肾上腺素转运的非常有效的抑制剂。异花青染料1,1'-二异丙基-2,4'-花青（双丙花青24）和1-甲基-1'-异丙基-2,4'-花青以及假异花青染料1,1'-二乙基-2,2'-花青（十甲花青22）和1-异丙基-1'-乙基-2,2'-花青（异丙花青22）最为有效，IC50分别为14、62、16和18 nmol/l。还在离体器官，即离体孵育的兔主动脉和离体灌注的大鼠心脏中测定了1-甲基-1'-异丙基-2,4'-花青对非神经元去甲肾上腺素转运的抑制效力。（摘要截短于250字）
