Studies on the cytochrome P450 catalyzed oxidation of 13C labeled 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine by 13C NMR

Bissel, Philippe; Castagnoli, Neal

doi:10.1016/j.bmc.2005.02.004

Cited by 6 publications

(2 citation statements)

References 31 publications

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“…In addition to the absence of dihydro intermediates, the absence of liver microsomal generated N-oxide metabolites for the N-alkyltetrahydroquinolines in the present study was another notable metabolism difference from the previously reported MPTP derivatives (Castagnoli et al, 2002;Bissel and Castagnoli, 2005) and other substructures somewhat similar to MPTP (Christensen et al, 1999;Dalvie and O'Connell, 2004). The active H/D exchange experiment provided evidence that none of the detected mono-oxidation metabolites of compound B were N-oxides.…”

Section: Discussioncontrasting

confidence: 69%

Metabolic Aromatization ofN-Alkyl-1,2,3,4-Tetrahydroquinoline Substructures to Quinolinium by Human Liver Microsomes and Horseradish Peroxidase

Gu¹,

Collins²,

Holsworth³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Metabolic aromatization of xenobiotics is an unusual reaction with some documented examples. For instance, the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to the neurotoxic pyridinium ion metabolite 1-methyl-4-phenylpyridinium by monoamine oxidase (MAO) B in the brain has been of interest to a number of investigators. It has also been reported that although the aromatization of N-methyl-tetrahydroisoquinoline occurs with MAO B, the metabolism does not proceed for its isomer, N-methyltetrahydroquinoline, by the same enzyme. The aromatization of an N-alkyl-tetrahydroquinoline substructure was identified during in vitro metabolite profiling of compound A, which was designed as a potent renin inhibitor for the treatment of hypertension. The Nalkylquinolinium metabolite of compound A was identified by liquid chromatography-tandem mass spectrometry of human liver microsomal incubates and proton NMR of the isolated metabolite.Further in vitro metabolism studies with a commercially available chemical (compound B), containing the same substructure, also generated an N-alkylquinolinium metabolite. In vitro cytochrome P450 (P450) reaction phenotyping of compound A revealed that the metabolism was catalyzed exclusively by CYP3A4. Although compound B was a substrate for several P450 isoforms, its quinolinium metabolite was also generated predominantly by CYP3A4. Neither compound A nor compound B was a substrate of MAOs. The quinolinium metabolites were readily produced by horseradish peroxidase, suggesting that aromatization of the N-alkyltetrahydroquinoline could occur via a mechanism involving single electron transfer from nitrogen. Although dihydro intermediates from the tetrahydroquinoline substrates were not observed in the formation of quinolinium metabolites, cyanide trapping results indicated the occurrence of iminium intermediates.Compound A (Scheme 1) was a lead compound, consisting of a novel nonpeptidic ketopiperazine-based scaffold, that was designed as a potent renin inhibitor for the treatment of hypertension (Holsworth et al., 2005(Holsworth et al., , 2006. The renin-angiotensin system (RAS) plays a key role in blood pressure regulation. Pharmacological blockade of the RAS cascade is usually achieved with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Renin inhibition has been sought for decades, as it would inhibit the initial and rate-limiting step of the RAS and hence might offer a therapeutic profile distinct from angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Recent progress shows new potential for the treatment of hypertension by renin inhibition (Fisher and Hollenberg, 2005;Wood et al., 2005).During in vitro metabolite profile studies on compound A, in support of lead optimization, an unusual metabolite was observed. It appeared to be derived from aromatization of the N-alkyltetrahydroquinoline ring, yielding an N-alkylquinolinium ion as a major metabolite in human liver microsomes. Similar metabolic oxidation of 1-methyl-4...

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Section: Discussioncontrasting

confidence: 69%

Metabolic Aromatization ofN-Alkyl-1,2,3,4-Tetrahydroquinoline Substructures to Quinolinium by Human Liver Microsomes and Horseradish Peroxidase

Gu¹,

Collins²,

Holsworth³

et al. 2006

Drug Metab Dispos

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“…Ring α‐carbon deprotonation of 1 •+ yields the neutral radical 2 • that undergoes further oxidation to the 2,3‐dihydropyridinium product 3H + 5, 6. An alternative proposal assumes an initial hydrogen atom transfer (HAT) step to yield 2 • directly 7–9. The second 2‐electron oxidation ( 3 → 4 + ) has not been characterized fully.…”

Section: Introductionmentioning

confidence: 99%

Mass spectrometric studies on 4‐aryl‐1‐cyclopropyl‐1,2‐dihydropyridinyl derivatives: an examination of a novel fragmentation pathway

et al. 2006

Self Cite

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Examination of the electrospray ionization product ion spectra of 1,2-dihydropyridinyl and 4-aryl-1,2-dihydropyridinyl derivatives bearing a 1-cyclopropyl or 1-trans-2-phenylcyclopropyl group has led to the characterization of unexpected fragment ions. For example, the base peak at m/z 156 present in the product ion spectrum of trans-1-(2-phenylcyclopropyl)-4-phenyl-1,2-dihydropyridine proved not to be the expected 4-phenylpyridinium species but rather the isomeric 3-phenyl-5-azoniafulvenyl species. The results of studies with a series of structural and isotopically labeled analogs require a novel fragmentation pathway to account for the formation of this and related fragment ions. One possible pathway is based on an initial 1,5-sigmatropic shift of a cyclopropylmethylene hydrogen atom that is accompanied by opening of the cyclopropyl ring. The resulting eniminium intermediates then fragment to yield the 5-azoniafulvenyl species.

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Detoxification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes: A theoretical investigation

Wang

Zheng

et al. 2016

Journal of Inorganic Biochemistry

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Studies on the cytochrome P450 catalyzed oxidation of 13C labeled 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine by 13C NMR

Cited by 6 publications

References 31 publications

Metabolic Aromatization ofN-Alkyl-1,2,3,4-Tetrahydroquinoline Substructures to Quinolinium by Human Liver Microsomes and Horseradish Peroxidase

Metabolic Aromatization ofN-Alkyl-1,2,3,4-Tetrahydroquinoline Substructures to Quinolinium by Human Liver Microsomes and Horseradish Peroxidase

Mass spectrometric studies on 4‐aryl‐1‐cyclopropyl‐1,2‐dihydropyridinyl derivatives: an examination of a novel fragmentation pathway

Detoxification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes: A theoretical investigation

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