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

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 (GABA_A) 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.