Department of Developmental Biology, Campus Box 8103, Washington University in St. Louis, School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
Bioorg Med Chem Lett. 2010 Nov 15;20(22):6680-4. doi: 10.1016/j.bmcl.2010.09.008. Epub 2010 Sep 15.
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 Δ(16)-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 Δ(16)-17-carbonitrile analogue both have potent anesthetic and receptor actions. The differential effect of the Δ(16)-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.
阿尔法羟酮，一种含有 17β-乙酰基的神经活性甾体，在人类中具有很强的麻醉活性。这种药理活性归因于该甾体增强γ-氨基丁酸 A 型受体的γ-氨基丁酸介导的氯电流。将阿尔法羟酮转化为 Δ(16)-阿尔法羟酮产生一种类似物，在人类中缺乏麻醉活性，并且受体作用大大减弱。相比之下，阿尔法羟酮的相应 17β-氰基类似物和 Δ(16)-17-氰基类似物都具有很强的麻醉和受体作用。Δ(16)-双键对阿尔法羟酮和 17β-氰基类似物作用的差异影响归因于对 17-乙酰基和 17-氰基取代基取向的差异影响。
