Summary
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-l′-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-l′-isopropyl-2,4′-cyanine was determined also in isolated organs, namely the isolated incubated rabbit aorta and the isolated perfused rat heart. The IC50's were 740 and 100 nmol/l, respectively. By contrast, the desipramine-sensitive neuronal type of noradrenaline transporter in PC 12 cells was hardly affected by the cyanine-related compounds. Decynium22 (3 μmol/l) inhibited the neuronal noradrenaline transporter of clonal PC12 cells by 14% only.
Cyanine-related compounds potently and selectively inhibit the extraneuronal transport mechanism for noradrenaline. They are expected to facilitate the functional and biochemical characterisation of the extraneuronal noradrenaline transporter.
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Supported by the Deutsche Forschungsgemeinschaft (SFB 176) and the Universitätsbund Würzburg
Correspondence to: H. Russ at the above address
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Russ, H., Sonna, J., Keppler, K. et al. Cyanine-related compounds: a novel class of potent inhibitors of extraneuronal noradrenaline transport. Naunyn-Schmiedeberg's Arch Pharmacol 348, 458–465 (1993). https://doi.org/10.1007/BF00173203
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DOI: https://doi.org/10.1007/BF00173203