5-Isothiocyanonicotine: a high-affinity irreversible ligand for brain nicotinic receptors.
A newly synthesized affinity ligand, (R,S)-5-isothiocyanonicotine (ISCN-N) was found to inhibit irreversibly the binding of [3H]methylcarbamylcholine (a specific nicotinic receptor ligand) to brain membranes. Plots of percent inhibition versus ligand concentration yielded an IC50 of 7 x 10(-8) M for SCN-N and Ki values of 6 x 10(-9) and 2 x 10(-9) M for (R,S)-5-aminonicotine and (S)-nicotine, respectively. The IC50 value for irreversible inhibition of [3H]methylcarbamylcholine by SCN-N was 2 x 10(-7) M. The affinity ligand irreversibly inhibited brain nicotinic receptors in vivo in a dose-dependent manner, the inhibition being 49% at a dose of 20 mumol/kg. Behavioral studies in mice revealed that SCN-N had less than one-fifth the potency of nicotine in producing muscle weakness and seizures, whereas 5-aminonicotine was without significant behavioral effects at doses up to 20 mumol/kg.
Department of Chemistry, University of Rochester, NY 14642.
K D
KD
Kim
N
N
Lerner-Marmarosh
M
M
Saraswati
A S
AS
Kende
L G
LG
Abood
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002217:Carbachol / Q000031:analogs & derivatives / Q000378:metabolism; D002417:Cattle; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D009538:Nicotine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D018733:Nicotinic Antagonists
D018733:Nicotinic Antagonists; C053765:N-methylcarbamylcholine; C087868:5-isothiocyanonicotine; D009538:Nicotine; D002217:Carbachol