Cyanine-related compounds: a novel class of potent inhibitors of extraneuronal noradrenaline transport.
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)
Russ
H
H
Department of Pharmacology, University of Würzburg, Germany.
Sonna
J
J
Keppler
K
K
Baunach
S
S
Schömig
E
E
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001120:Arginine / Q000378:metabolism; D002460:Cell Line; D005260:Female; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D016716:PC12 Cells; D011804:Quinolines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013256:Steroids / Q000378:metabolism; D014343:Trypan Blue
D014179:Neurotransmitter Uptake Inhibitors; D011804:Quinolines; D013256:Steroids; C100254:pseudoisocyanine; D001120:Arginine; D014343:Trypan Blue; D009638:Norepinephrine