Discovery of non-Zwitterionic GABAA receptor full agonists and a superagonist

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Abstract

Numerous previous studies of GABAA receptor ligands have suggested that GABAA receptor agonists must be zwitterionic and feature an intercharge separation similar to that of GABA (approx. 4.7–6 Å). In this communication we demonstrate that appropriately functionalized GABA amides are partial, full, or superagonists, despite their non-zwitterionic structure.

Functional assays (chloride flux) demonstrate that appropriately functionalized GABA amides are partial, full, or superagonists of the GABAA receptor.

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Acknowledgements

We thank the Virginia Tech Departments of Chemistry and Entomology for financial support.

References (34)

  • G.B Smith et al.

    Trends Pharm. Sci.

    (1995)
  • M.D Luu et al.

    Life Sci.

    (1987)
  • B Ebert et al.

    Bioorg. Med. Chem. Lett.

    (2001)
  • L Li et al.

    Chem. Biol.

    (2001)
  • C.F Saller et al.

    J. Chromatogr.

    (1989)
  • J.R Bloomquist et al.

    Biochem. Biophys. Res. Commun.

    (1985)
  • J.G Newell et al.

    J. Biol. Chem.

    (2000)
  • J Borman

    Trends Pharm. Sci.

    (2000)
  • P Krogsgaard-Larsen et al.

    J. Med. Chem.

    (1994)
  • M Lancel et al.

    Angew. Chem., Int. Ed.

    (1999)
  • Krogsgaard-Larsen, P.; Honoré, T.; Thyssen, K. In GABA-Neuro-transmitters; Krogsgaard-Larsen, P., Scheel-Krüger, J.,...
  • P Krogsgaard-Larsen et al.

    J. Neurochem.

    (1982)
  • E Falch et al.

    Eur. J. Med. Chem.

    (1985)
  • E Falch et al.

    J. Neurochem.

    (1985)
  • Krogsgaard-Larsen, P.; Falch, E.; Hjeds, H. In Progress in Medicinal Chemistry; Ellis, G. P., West, G. B., Eds.;...
  • Krogsgaard-Larsen, P.; Hjeds, H.; Falch, E.; Jorgensen, F. S.; Nielsen, L. In Advances in Drug Research; Testa, B.,...
  • R.M Woodward et al.

    Mol. Pharmacol.

    (1993)
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