CYANINE-RELATED COMPOUNDS - A NOVEL CLASS OF POTENT INHIBITORS OF EXTRANEURONAL NORADRENALINE TRANSPORT

The neurotransmitter noradrenaline is removed from the extracellular s pace by neuronal and extraneuronal transport mechanisms. In the past, further functional and biochemical characterisation of the corticoster one-sensitive extraneuronal transporter was hampered by the lack of hi ghly potent inhibitors. Here we describe a new class of selective and highly potent inhibitors of the extraneuronal noradrenaline transporte r. Clonal Caki-1 cells possess the human type of extraneuronal noradre naline carrier. The effect of various steroids and steroid-like compou nds on initial rates of specific H-3-noradrenaline transport in Caki-1 cells was investigated. None of these steroids had an inhibitory pote ncy higher than that of corticosterone which hitherto was generally ac cepted 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 transport er. Several cationic quinolines that belong to the chemical class of t he cyanine dyes turned out to be very potent inhibitors of H-3-noradre naline 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) a nd 1-isopropyl-1'-ethyl-2,2'-cyanine (iprecynium22) were most potent w ith IC50's of 14, 62, 16, and 18 nmol/l, respectively. The inhibitory potency on extraneuronal noradrenaline transport of 1-methyl-1'-isopro pyl-2,4'-cyanine was determined also in isolated organs, namely the is olated incubated rabbit aorta and the isolated perfused rat heart. The IC50's were 740 and 100 nmol/l, respectively. By contrast, the desipr amine-sensitive neuronal type of noradrenaline transporter in PC12 cel ls was hardly affected by the cyanine-related compounds. Decynium22 (3 mumol/l) inhibited the neuronal noradrenaline transporter of clonal P C12 cells by 14% only. Cyanine-related compounds potently and selectiv ely inhibit the extraneuronal transport mechanism for noradrenaline. T hey are expected to facilitate the functional and biochemical characte risation of the extraneuronal noradrenaline transporter.