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5-Isothiocyanonicotine: a high-affinity irreversible ligand for brain nicotinic receptors
K D Kim1, N Lerner-Marmarosh, M Saraswati
1Department of Chemistry, University of Rochester, NY 14642.
Abstract:
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.