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Research ArticleArticle

Influence of Lipophilicity on the Interactions ofN-Alkyl-4-phenyl-1,2,3,6-tetrahydropyridines and Their Positively Charged N-Alkyl-4-phenylpyridinium Metabolites with Cytochrome P450 2D6

Amit S. Kalgutkar, Sue Zhou, Odette A. Fahmi and Timothy J. Taylor
Drug Metabolism and Disposition May 2003, 31 (5) 596-605; DOI: https://doi.org/10.1124/dmd.31.5.596
Amit S. Kalgutkar
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Sue Zhou
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Odette A. Fahmi
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Timothy J. Taylor
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Abstract

The relationship between lipophilicity and CYP2D6 affinity of cyclic tertiary (N-alkyl-4-phenyl-1,2,3,6-tetrahydropyridines) and quaternary (N-alkyl-4-phenylpyridinium) amines was examined. The 1,2,3,6-tetrahydropyridine scaffold was chosen due to its common occurrence in the structures of CYP2D6 ligands such as the Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the dehydrated haloperidol metaboliteN-[4-(4-fluorophenyl)-4-oxobutyl]-4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (HPTP). Likewise, the pyridinium framework is found in and 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium andN-methyl-4-phenylpyridinium (MPP+), the positively charged metabolites of MPTP and haloperidol. The lack of CYP2D6 inhibition by MPTP and its pyridinium metabolite MPP+ was due to their hydrophilic nature since higherN-alkyl homologs revealed substantial increases in inhibitory potency against recombinant CYP2D6-mediated bufuralol-1′-hydroxylation. The reasonable correlation between lipophilicity and CYP2D6 inhibition by pyridiniums and 1,2,3,6-tetrahydropyridines was only limited to straight chainN-alkyl analogs, since certainN-alkylaryl analogs of lower lipophilicity were better CYP2D6 inhibitors. CYP2D6 substrate properties of straight chainN-alkyltetrahydropyridines were also governed by lipophilicity, andN-heptyl-4-phenyl-1,2,3,6-tetrahydropyridine was the optimal substrate (Kmapp = 0.63 μM). Metabolism studies indicated that the N-heptyl analog underwent monohydroxylation on the aromatic ring and on theN-heptyl group suggesting that 1,2,3,6-tetrahydropyridines can bind in more than one conformation in the CYP2D6 active site. Increased lipophilicity of haloperidol metabolites did not correlate with inhibitory potency since the more lipophilic HPTP metabolite was less potent as an inhibitor than reduced-haloperidol and reduced-HPTP. Furthermore, HPTP and reduced-HPTP, of comparable lipophilicity to theN-heptyltetrahydropyridine analog were inactive as CYP2D6 substrates. This observation suggests that steric constraints rather than lipophilicity are responsible for the lack of CYP2D6 substrate properties of cyclic tertiary amines tethered to bulkyN-substituents. This phenomenon appears to be a common theme among several cyclic tertiary amine-containing anti-depressants and should be taken into consideration when designing central nervous system agents devoid of CYP2D6 substrate properties.

Footnotes

  • Abbreviations used are::
    QSAR
    quantitative structure-activity relationship
    MPTP
    N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    MPP+
    N-methyl-4-phenylpyridinium
    PTP
    4-phenyl-1,2,3,6-tetrahydropyridine
    HP
    haloperidol, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4-piperdinol
    HPTP
    N-[4-(4-fluorophenyl)-4-oxobutyl]-4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine
    HPP+
    4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium
    (±)-RHP
    (±)-4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-hydroxybutyl]-4-piperdinol
    (±)-RHPTP
    (±)-4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-hydroxybutyl]-1,2,3,6-tetrahydropyridine
    CID
    collision-induced dissociation
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    cLog P
    calculated log P
    Rt
    retention time
    SAR
    structure-activity relationship
    DMSO
    dimethyl sulfoxide
    • Received November 26, 2002.
    • Accepted January 30, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (5)
Drug Metabolism and Disposition
Vol. 31, Issue 5
1 May 2003
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Influence of Lipophilicity on the Interactions ofN-Alkyl-4-phenyl-1,2,3,6-tetrahydropyridines and Their Positively Charged N-Alkyl-4-phenylpyridinium Metabolites with Cytochrome P450 2D6
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Research ArticleArticle

Influence of Lipophilicity on the Interactions ofN-Alkyl-4-phenyl-1,2,3,6-tetrahydropyridines and Their Positively Charged N-Alkyl-4-phenylpyridinium Metabolites with Cytochrome P450 2D6

Amit S. Kalgutkar, Sue Zhou, Odette A. Fahmi and Timothy J. Taylor
Drug Metabolism and Disposition May 1, 2003, 31 (5) 596-605; DOI: https://doi.org/10.1124/dmd.31.5.596

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Research ArticleArticle

Influence of Lipophilicity on the Interactions ofN-Alkyl-4-phenyl-1,2,3,6-tetrahydropyridines and Their Positively Charged N-Alkyl-4-phenylpyridinium Metabolites with Cytochrome P450 2D6

Amit S. Kalgutkar, Sue Zhou, Odette A. Fahmi and Timothy J. Taylor
Drug Metabolism and Disposition May 1, 2003, 31 (5) 596-605; DOI: https://doi.org/10.1124/dmd.31.5.596
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