Neurosteroid analogues. 15. A comparative study of the anesthetic and GABAergic actions of alphaxalone, Δ16-alphaxalone and their corresponding 17-carbonitrile analogues

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Abstract

Alphaxalone, a neuroactive steroid containing a 17β-acetyl group, has potent anesthetic activity in humans. This pharmacological activity is attributed to this steroid’s enhancement of γ-amino butyric acid-mediated chloride currents at γ-amino butyric acid type A receptors. The conversion of alphaxalone into Δ16-alphaxalone produces an analogue that lacks anesthetic activity in humans and that has greatly diminished receptor actions. By contrast, the corresponding 17β-carbonitrile analogue of alphaxalone and the Δ16-17-carbonitrile analogue both have potent anesthetic and receptor actions. The differential effect of the Δ16-double bond on the actions of alphaxalone and the 17β-carbonitrile analogue is accounted for by a differential effect on the orientation of the 17-acetyl and 17-carbonitrile substituents.

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Acknowledgments

This work was supported by NIH Grant GM47969 (D.F.C., A.S.E., C.F.Z.) and the Bantly Foundation. X-ray crystal structures were made possible by NSF Shared Instrument Grant No. CHE-042097.

References and notes (27)

  • G.H. Phillipps

    J. Steroid Biochem.

    (1975)
  • A.G. Lee

    Biochem. Pharmacol.

    (1979)
  • A. Makriyannis et al.

    Biochim. Biophys. Acta

    (1986)
  • T. Mavromoustakos et al.

    Biochim. Biophys. Acta

    (1994)
  • T. Mavromoustakos et al.

    Biochim. Biophys. Acta

    (1995)
  • T. Mavromoustakos et al.

    Biochim. Biophys. Acta

    (1997)
  • L. Gyermek et al.

    Anesthesiology

    (1975)
  • R.M. Atkinson et al.

    J. Med. Chem.

    (1965)
  • G.H. Phillipps
  • D.K. Lawrence et al.

    Mol. Pharmacol.

    (1975)
  • A. Makriyannis et al.

    J. Neurosci. Res.

    (1980)
  • A. Makriyannis et al.

    J. Med. Chem.

    (1983)
  • T.J. O’Leary et al.

    Biochemistry

    (1984)
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