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Research ArticleArticle

Influence of N-Substitution of 7-Methoxy-4-(aminomethyl)-coumarin on Cytochrome P450 Metabolism and Selectivity

Jennifer Venhorst, Rob C. A. Onderwater, John H. N. Meerman, Jan N. M. Commandeur and Nico P. E. Vermeulen
Drug Metabolism and Disposition December 2000, 28 (12) 1524-1532;
Jennifer Venhorst
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Rob C. A. Onderwater
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John H. N. Meerman
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Jan N. M. Commandeur
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Nico P. E. Vermeulen
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Abstract

A series of six structural analogs of 7-methoxy-4-(aminomethyl)-coumarin (MAMC), a recently developed high-throughput substrate of P450 2D6 (CYP2D6), was synthesized to investigate the influence of N-substitution on the metabolism by cytochrome P450s, as well as on P450 selectivity. The analogs were obtained by introducing alkyl substituents at the amino group of MAMC and by replacing this moiety with a pyridine group. Competition experiments using heterologously expressed CYP2D6 demonstrated that the introduction and elongation of alkyl substituents strongly decreased the IC50 values toward dextromethorphanO-demethylation. Metabolism studies showed that the regioselectivity of metabolism was unaffected by the varyingN substituents, as only O-dealkylation of the analogs and no N-dealkylation was observed. In excellent agreement with the competition experiments, metabolism studies also showed that elongation of the alkyl chain dramatically increased the affinity of the compounds toward CYP2D6, as indicated by an up to 100-fold decrease in Km values. TheVmax values displayed a much less pronounced decrease with an increasing N-alkyl chain, resulting in as much as a 30-fold increase in theVmax/Km value. Interestingly, due to the higher fluorescent yield of theN-alkyl metabolites compared with the metabolite of MAMC, O-dealkylation of N-methyl MAMC by CYP2D6 can be measured with a more than 3-fold higher sensitivity. Studies on P450 selectivity showed that only CYP1A2 and CYP2D6 contribute to the O-dealkylation of theN-alkyl analogs in both heterologously expressed P450s and human liver microsomes. In sharp contrast to CYP2D6,N-alkylation of MAMC did not significantly affect theKm values of O-dealkylation by CYP1A2, but it did result in higher Vmaxvalues. Finally, CYP1A2 also N-dealkylated the analogs.

Footnotes

  • Send reprint requests to: Nico P. E. Vermeulen, Division of Molecular Toxicology, Department of Pharmacochemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. E-mail: vermeule{at}chem.vu.nl

  • Abbreviations used are::
    CYP or P450
    cytochrome P450
    MAMC
    7-methoxy-4-(aminomethyl)-coumarin
    MMAMC
    N-methyl 7-methoxy-4-(aminomethyl)-coumarin
    diMMAMC
    N,N-dimethyl 7-methoxy-4-(aminomethyl)-coumarin
    EMAMC
    N-ethyl 7-methoxy-4-(aminomethyl)-coumarin
    PMAMC
    N-propyl 7-methoxy-4-(aminomethyl)-coumarin
    BMAMC
    N-butyl 7-methoxy-4-(aminomethyl)-coumarin
    MMPyrC
    7-methoxy-4-(methylpyridinium)-coumarin
    HAMC
    7-hydroxy-4-(aminomethyl)-coumarin
    MHAMC
    N-methyl 7-hydroxy-4-(aminomethyl)-coumarin
    diMHAMC
    N,N-dimethyl 7-hydroxy-4-(aminomethyl)-coumarin
    EHAMC
    N-ethyl 7-hydroxy-4-(aminomethyl)-coumarin
    PHAMC
    N-propyl 7-hydroxy-4-(aminomethyl)-coumarin
    BHAMC
    N-butyl 7-hydroxy-4-(aminomethyl)-coumarin
    HMPyrC
    7-hydroxy-4-(methylpyridinium)-coumarin
    • Received April 25, 2000.
    • Accepted August 15, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (12)
Drug Metabolism and Disposition
Vol. 28, Issue 12
1 Dec 2000
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Research ArticleArticle

Influence of N-Substitution of 7-Methoxy-4-(aminomethyl)-coumarin on Cytochrome P450 Metabolism and Selectivity

Jennifer Venhorst, Rob C. A. Onderwater, John H. N. Meerman, Jan N. M. Commandeur and Nico P. E. Vermeulen
Drug Metabolism and Disposition December 1, 2000, 28 (12) 1524-1532;

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Research ArticleArticle

Influence of N-Substitution of 7-Methoxy-4-(aminomethyl)-coumarin on Cytochrome P450 Metabolism and Selectivity

Jennifer Venhorst, Rob C. A. Onderwater, John H. N. Meerman, Jan N. M. Commandeur and Nico P. E. Vermeulen
Drug Metabolism and Disposition December 1, 2000, 28 (12) 1524-1532;
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