Neurosteroid Analogues. 16. A New Explanation for the Lack of Anesthetic Effects of Delta(16)-Alphaxalone and Identification of a Delta(17(20)) Analogue with Potent Anesthetic Activity

作者：Stastna Eva; Krishnan Kathiresan; Manion Brad D; Taylor Amanda; Rath Nigam P; Chen Zi Wei; Evers Alex S; Zorumski Charles F; Mennerick Steven; Covey Douglas F^*

来源：Journal of Medicinal Chemistry, 2011, 54(11): 3926-3934.

DOI：10.1021/jm2002487

This study addresses the hypothesis that the lack of anesthetic activity for (3 alpha,5 alpha)-3-hydroxypregn-16-ene-11,20-dione (e-alphaxalone) is explained by the steroid Delta(16) double bond constraining the steroid 20-carbonyl group to a position that prevents it from favorably interacting with gamma-aminobutyric acid type A (GABA(A)) receptors. A series of Delta(16) and Delta(17(20)) analogues of Delta(16)-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 Delta(16)-alphaxalone, not the location of the constrained C-20 carbonyl group, that prevents Delta(16)-alphaxalone from interacting strongly with the GABA(A) receptor and having anesthetic activity. Consistent with this conclusion, a Delta(17(20)) analogue of Delta(16)-alphaxalone without a C-21 methyl group was found to be very similar to the anesthetic steroid (3 alpha,5 alpha)-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.

• 出版日期2011-6-9