ISOCYANINES AND PSEUDOISOCYANINES AS A NOVEL CLASS OF POTENT NORADRENALINE TRANSPORT INHIBITORS - SYNTHESIS, DETECTION, AND BIOLOGICAL-ACTIVITY

Noradrenaline, the neurotransmitter of the sympathetic nervous system, is removed from the extracellular space by both neuronal and extraneu ronal transport mechanisms. In the past, further investigation of the extraneuronal type of noradrenaline transporter was severely hampered by the lack of potent inhibitors. Here, we describe the synthesis of v arious novel noradrenaline transport inhibitors which belong to the ch emical class of isocyanine and pseudoisocyanine dyes. The biological a ctivity of these compounds was investigated in a tissue culture system (Caki-1 cells). 1,1'-Diisopropyl-2,4'-cyanine, 1,1'-diethyl-2,2'-cyan ine, and 1-ethyl-1'-isopropyl-2,2'-cyanine turned out as the most pote nt inhibitors of the extraneuronal noradrenaline transport known so fa r. At 100 nmol/L, these compounds diminished extraneuronal noradrenali ne transport by about 95%. Their IC50's were below 20 nmol/L. In addit ion, a rapid and sensitive method (based on HPLC with fluorometric det ection) to measure these compounds in body fluids is reported.