Discovery of non-peptide, small molecule antagonists of α9α10 nicotinic acetylcholine receptors as novel analgesics for the treatment of neuropathic and tonic inflammatory pain

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Abstract

A series of azaaromatic quaternary ammonium analogs has been discovered as potent and selective α9α10 nicotinic acetylcholine receptor (nAChR) antagonists. The preliminary structure–activity relationships of these analogs suggest that increased rigidity in the linker units results in higher potency in inhibition of α9α10 nAChRs and greater selectivity over α7 nAChRs. These analogs represent a new class of analgesic for the treatment of neuropathic and tonic inflammatory pain.

Graphical abstract

A series of azaaromatic quaternary ammonium analogs has been discovered as potent and selective α9α10 nicotinic acetylcholine receptor (nAChR) antagonists. The preliminary structure–activity relationships of these analogs suggest that increased rigidity in the linker units results in higher potency in inhibition of α9α10 nAChRs and greater selectivity over α7 nAChRs. These analogs represent a new class of analgesic for the treatment of neuropathic and tonic inflammatory pain.

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Acknowledgment

This work was supported by NIH (Grant U19DA017548 to L.P.D. and P.A.C., MH53631 and GM48677 to J.M.M.) and a seed grant from the University of Utah Research Foundation to J.M.M.

References and notes (30)

  • M.O. Ortells et al.

    Trends Neurosci.

    (1995)
  • J. Changeux et al.

    Curr. Opin. Neurobiol.

    (2001)
  • A.B. Elgoyhen et al.

    Cell

    (1994)
  • J.M. McIntosh et al.

    Biochem. Pharmacol.

    (2009)
  • J.M. McIntosh et al.

    J. Biol. Chem.

    (2005)
  • J.M. McIntosh et al.

    Biochem. Pharmacol.

    (2009)
  • J.T. Ayers et al.

    Bioorg. Med. Chem. Lett.

    (2002)
  • G.R. Zheng et al.

    Bioorg. Med. Chem. Lett.

    (2007)
  • G.R. Zheng et al.

    Bioorg. Med. Chem. Lett.

    (2007)
  • Z.F. Zhang et al.

    Bioorg. Med. Chem. Lett.

    (2008)
  • J.R. Holtman et al.

    J. Pain

    (2010)
  • N. Le Novere et al.

    J. Mol. Evol.

    (1995)
  • E.X. Albuquerque et al.

    Physiol. Rev.

    (2009)
  • R. Nashmi et al.

    J. Mol. Neurosci.

    (2006)
  • A.B. Elgoyhen et al.

    Proc. Natl. Acad. Sci. U.S.A.

    (2001)
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