The synthesis and biological evaluation of dopamine transporter inhibiting activity of substituted diphenylmethoxypiperidines

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Abstract

The synthesis of potent 4-aryl methoxypiperidinol inhibitors of the dopamine transporter is described. Symmetrical para substituents of the benzene rings are important for high potency in binding to the dopamine transporter. 4-[Bis(4-fluorophenyl) methoxy]-1-methylpiperidine has an IC50 of 22.1 ± 5.73 nM and increases locomotor activity in mice.

Graphical abstract

The development of potent 4-(arylmethoxy)-1-alkylpiperidine inhibitors of the dopamine transporter is described. Symmetrical para substituents of the benzene rings are important for high potency in binding to the dopamine transporter. 3b has an IC50 = 22.1 ± 5.73 nM and elevates locomotor activity in mice, 3g has an IC50 = 12.1 ± 7.51 nM and is inactive in this test.

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Acknowledgments

This work was supported by Wake Forest University School of Medicine Venture Funds, National Center for Minority Health and Health Disparities Grant MD00232 and National Institutes of Health Grant AA014091.

References and notes (18)

  • N.D. Volkow et al.

    Biol. Psychiatry

    (2005)
  • E.A. Budygin et al.

    Neurosci. Lett.

    (2000)
  • G.B. Lapa et al.

    Eur. J. Pharmacol.

    (2005)
  • A.K. Dutta et al.

    Eur. J. Pharmacol.

    (2003)
  • G.E. Torres et al.

    Neuroscience

    (2003)
  • Y. Mateo et al.

    Eur. J. Neurosci.

    (2004)
  • S. Singh

    Chem. Rev.

    (2000)
  • F.I. Carroll et al.

    J. Med. Chem.

    (1999)
  • R.I. Dessai et al.

    J. Neurosci.

    (2005)
There are more references available in the full text version of this article.

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