Neurosteroid analogues. 16. A new explanation for the lack of anesthetic effects of Δ16-alphaxalone and identification of a Δ17(20) analogue with potent anesthetic activity

Eva Stastna, Kathiresan Krishnan, Brad D. Manion, Amanda Taylor, Nigam P. Rath, Zi Wei Chen, Alex S. Evers, Charles F. Zorumski, Steven Mennerick, Douglas F. Covey

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Abstract

This study addresses the hypothesis that the lack of anesthetic activity for (3α,5α)-3-hydroxypregn-16-ene-11,20- dione (Δ 16-alphaxalone) is explained by the steroid Δ16 double bond constraining the steroid 20-carbonyl group to a position that prevents it from favorably interacting with γ-aminobutyric acid type A (GABAA) receptors. A series of Δ16 and Δ17(20) analogues of Δ16-alphaxalone was prepared to evaluate this hypothesis in binding, electrophysiological, and tadpole anesthesia experiments. The results obtained failed to support the hypothesis. Instead, the results indicate that it is the presence of the C-21 methyl group in Δ16-alphaxalone, not the location of the constrained C-20 carbonyl group, that prevents ?16-alphaxalone from interacting strongly with the GABAA receptor and having anesthetic activity. Consistent with this conclusion, a Δ17(20) analogue of Δ16- alphaxalone without a C-21 methyl group was found to be very similar to the anesthetic steroid (3α,5α)-3-hydroxypregnane-11,20-dione (alphaxalone) with regard to time of onset and rate of recovery from anesthesia when administered to mice by tail vein injection.

Original languageEnglish
Pages (from-to)3926-3934
Number of pages9
JournalJournal of Medicinal Chemistry
Volume54
Issue number11
DOIs
StatePublished - Jun 9 2011

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