The evidence implicating the formation of iminium ions as reactive intermediates in the metabolism of alicyclic amines has been reviewed. The mechanism of formation of iminium ions and their conversion to alpha-carbonyl compounds or demethylated amines is discussed. The use of a simple cyanide trapping technique for iminium ions has been demonstrated to monitor a large number of alicyclic drugs for iminium ion formation. The possible role of iminium ions in the pharmacology and toxicology of alicyclic amines is considered.
The role of nitric oxide (NO) in striatal dopamine release has been controversial. Most NO synthase inhibitors affect more than one isoform of the enzyme and exert vasoconstrictor effects which may also affect striatal dopamine function. We now report on the effect of a soluble monosodium salt of the selective brain NO synthase inhibitor 7-nitro indazole (7-NINA). Using 7-NINA the first study of selective inhibition of the brain isoform of NO synthase on dopamine efflux in rat striatum was undertaken by use of in vivo microdialysis. Perfusion with 7-NINA (1 mM) increased striatal dopamine efflux. The effect of 7-NINA was partially antagonized (67%) by co-perfusion with L-arginine (1 mM), the precursor of NO formation in vivo. This suggests that 7-NINA induces a competitive inhibition of NO synthase activity. These data show that endogenous NO has an inhibitory effect on striatal dopamine efflux in vivo.
The metabolism of (-)-(S)-nicotine has been investigated following intratracheal administration to the recirculating perfused rabbit lung model. The metabolic products present in the perfusate were identified by co-chromatography (HPLC and GC) with authentic standards and quantified by HPLC. After the 180 min perfusion period, nicotine was found to be metabolically transformed to cotinine (33.7%), 3-hydroxycotinine (10.4%), cotinine-1-N-oxide (3.4%) and nicotine-1'-N-oxide (14.4%). Norcotinine, nornicotine, 3-pyridyl-4-oxo-N-methylbutyramide and an uncharacterised metabolite were also detected in low amounts. Following the perfusion experiment, part of the lung tissue was homogenised in the presence of [14C]-sodium cyanide. Subsequent analysis of the homogenates indicated the formation of 2'-cyanonicotine, 1'-cyanomethylnornicotine and the diastereoisomeric 5'-cyanonicotines.
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