Synthesis, Structure and Stability of Nicotine Delta1'(5') Iminium Ion, an Intermediary Metabolite of Nicotine.

Brandänge, Svante; Lindblom, Lars; Fetter, J.; Lempert, K.; Møller, Jørgen; Folkers, Karl; Yanaihara, Noboru; Yanaihara, Chizuko

doi:10.3891/acta.chem.scand.33b-0187

Cited by 40 publications

(19 citation statements)

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“…The pK of this equilibrium was approximately 11.7. This value is considerably greater than that previously measured for nicotine ⌬1Ј(5Ј) iminium ion (pK Ϸ 8.4; Brandange and Lindblom, 1979). It is proposed that the greater pK for nomifensine dihydroisiquinolinium ion versus nicotine iminium ion is due to the conjugation of the iminum double bond to the aromatic ring as well as the aniline nitrogen for nomifensine.…”

Section: Discussioncontrasting

confidence: 49%

“…Stabilization of the iminium form can be derived from the resonance stabilization imparted by the aniline ring. Other iminium ion-carbinolamine equilibria can occur at lower pH values when the iminium ion does not possess any special stabilization, such as that of the iminium ion metabolite of nicotine (Brandange and Lindblom, 1979).…”

Section: Metabolism Of Nomifensine In Vitromentioning

confidence: 99%

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Metabolism of Nomifensine to a Dihydroisoquinolinium Ion Metabolite by Human Myeloperoxidase, Hemoglobin, Monoamine Oxidase A, and Cytochrome P450 Enzymes

Obach¹,

Dalvie²

2006

Drug Metab Dispos

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ABSTRACT:Nomifensine is an antidepressant agent that was removed from use because of a high incidence of hemolytic anemia. It contains an N-methyl-8-aminotetrahydroisoquinoline ring which has the potential to be oxidized to quaternary dihydroisoquinolinium and isoquinolinium ions, albeit such a transformation had not been previously observed. In this report, we demonstrate the conversion of nomifensine to a dihydroisoquinolinium ion metabolite by several human enzymes. Human liver microsomes supplemented with NADPH generated the dihydroisoquinolinium ion metabolite along with other hydroxylated metabolites, whereas when supplemented with t-butyl peroxide, only the dihydroisoquinolinium ion metabolite was observed. Monoamine oxidase A, but not monoamine oxidase B, catalyzed this reaction, as well as human hemoglobin supplemented with H 2 O 2 . Human myeloperoxidase catalyzed this reaction in the presence of H 2 O 2 , and activation of the reaction was observed when incubations were conducted in the presence of acetaminophen at concentrations relevant to those measured in humans. The reaction was also observed in human whole blood. The equilibrium between the dihydroisoquinolinium ion and carbinolamine was shown to have a pK of about 11.7. The dihydroisoquinolinium ion was shown to react with cyanide and borohydride, but not glutathione. These findings suggest that the electrophilic nomifensine dihydroisoquinolinium metabolite, which can be generated by several enzymes, could be behind toxic responses to nomifensine such as hemolytic anemia and hepatotoxicity.

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Section: Discussioncontrasting

confidence: 49%

Section: Metabolism Of Nomifensine In Vitromentioning

confidence: 99%

Metabolism of Nomifensine to a Dihydroisoquinolinium Ion Metabolite by Human Myeloperoxidase, Hemoglobin, Monoamine Oxidase A, and Cytochrome P450 Enzymes

Obach¹,

Dalvie²

2006

Drug Metab Dispos

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“…This transformation involves two steps. The first is mediated by a cytochrome P450 system to produce nicotine-⌬ 1Ј(5Ј) -iminium ion, which is in equilibrium with 5Ј-hydroxynicotine (Murphy, 1973;Brandange and Lindblom, 1979b;Peterson et al, 1987). The second step is catalyzed by a cytoplasmic aldehyde oxidase (Brandange and Lindblom, 1979a;Gorrod and Hibberd, 1982).…”

Section: A Primary Metabolites Of Nicotinementioning

confidence: 99%

Metabolism and Disposition Kinetics of Nicotine

2005

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“…Cyanide adducts have been observed for several other amine drugs when incubated with liver microsomes (Gorrod et al, 1991). In addition, for nicotine iminium ion, the adduct formed between hydroxide ion and the iminium ion is also observed at pH greater than 7.5 (Brandange and Lindblom, 1979). However, for the elzasonan indole iminium ion metabolite, such an adduct (carbinolamine) was not formed until the pH was raised above 9.5 as assessed by an examination of the UV/VIS spectrum at different pH values, indicating that the elzasonan indole iminium ion metabolite may be less reactive to adduct formation than nicotine or phencyclidine iminium ions.…”

Section: Discussionmentioning

confidence: 86%

“…The two forms coexist in physiological pH (7.4) and weakly alkaline pH range, whereas the carbinolamine exists in strong alkaline media. The nicotine iminium ion metabolite and its carbinol (5Ј-hydroxynicotine) metabolite have been reported to coexist in weakly alkaline conditions, and at the pH of cytoplasm (7.4) the carbinol form was estimated at approximately 25% (Brandange and Lindblom, 1979). Therefore, it is reasonably to assume that at physiological pH elzasonan carbinolamine and iminium ion equilibrium will shift toward the formation of the iminium ion metabolite.…”

Section: Discussionmentioning

confidence: 99%

Metabolism, Pharmacokinetics, and Excretion of the 5-Hydroxytryptamine_1BReceptor Antagonist Elzasonan in Humans

Kamel¹,

Obach²,

Colizza³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The metabolism, pharmacokinetics, and excretion of a potent and selective 5-hydroxytryptamine 1B receptor antagonist elzasonan have been studied in six healthy male human subjects after oral administration of a single 10-mg dose of [ 14 C]elzasonan. Total recovery of the administered dose was 79% with approximately 58 and 21% of the administered radioactive dose excreted in feces and urine, respectively. The average t 1/2 for elzasonan was 31.5 h. Elzasonan was extensively metabolized, and excreta and plasma were analyzed using mass spectrometry and NMR spectroscopy to elucidate the structures of metabolites. The major component of drug-related material in the excreta was in the feces and was identified as 5-hydroxyelzasonan (M3), which accounted for approximately 34% of the administered dose. The major human circulating metabolite was identified as the novel cyclized indole metabolite (M6) and accounted for ϳ65% of the total radioactivity. A mechanism for the formation of M6 is proposed. Furthermore, metabolism-dependent covalent binding of drug-related material was observed upon incubation of [ 14 C]elzasonan with liver microsomes, and data suggest that an indole iminium ion is involved. Overall, the major metabolic pathways of elzasonan were due to aromatic hydroxylation(s) of the benzylidene moiety, N-oxidation at the piperazine ring, N-demethylation, indirect glucuronidation, and oxidation, ring closure, and subsequent rearrangement to form M6.

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Synthesis, Structure and Stability of Nicotine Delta1'(5') Iminium Ion, an Intermediary Metabolite of Nicotine.

Cited by 40 publications

References 0 publications

Metabolism of Nomifensine to a Dihydroisoquinolinium Ion Metabolite by Human Myeloperoxidase, Hemoglobin, Monoamine Oxidase A, and Cytochrome P450 Enzymes

Metabolism of Nomifensine to a Dihydroisoquinolinium Ion Metabolite by Human Myeloperoxidase, Hemoglobin, Monoamine Oxidase A, and Cytochrome P450 Enzymes

Metabolism and Disposition Kinetics of Nicotine

Metabolism, Pharmacokinetics, and Excretion of the 5-Hydroxytryptamine_1BReceptor Antagonist Elzasonan in Humans

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Synthesis, Structure and Stability of Nicotine Delta1'(5') Iminium Ion, an Intermediary Metabolite of Nicotine.

Cited by 40 publications

References 0 publications

Metabolism of Nomifensine to a Dihydroisoquinolinium Ion Metabolite by Human Myeloperoxidase, Hemoglobin, Monoamine Oxidase A, and Cytochrome P450 Enzymes

Metabolism of Nomifensine to a Dihydroisoquinolinium Ion Metabolite by Human Myeloperoxidase, Hemoglobin, Monoamine Oxidase A, and Cytochrome P450 Enzymes

Metabolism and Disposition Kinetics of Nicotine

Metabolism, Pharmacokinetics, and Excretion of the 5-Hydroxytryptamine1BReceptor Antagonist Elzasonan in Humans

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Metabolism, Pharmacokinetics, and Excretion of the 5-Hydroxytryptamine_1BReceptor Antagonist Elzasonan in Humans