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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:20

Article

Bandyopadhyaya, Achintya K.¹  Manion, Brad D.²  Benz, Ann³  Taylor, Amanda³  Rath, Nigam P.^5,6  Evers, Alex S.^1,2  Zorumski, Charles F.^3,4  Mennerick, Steven^3,4  Covey, Douglas F.¹ 

[1] Washington Univ, Dept Dev Biol, Sch Med, St Louis, MO 63110 USA

[2] Washington Univ, Dept Anesthesiol, Sch Med, St Louis, MO 63110 USA

[3] Washington Univ, Dept Psychiat, Sch Med, St Louis, MO 63110 USA

[4] Washington Univ, Dept Anat & Neurobiol, Sch Med, St Louis, MO 63110 USA

[5] Univ Missouri, Dept Chem & Biochem, St Louis, MO 63121 USA

[6] Univ Missouri, Ctr Nanosci, St Louis, MO 63121 USA

关键词: Alphaxalone;    Anesthetic steroid;    Delta-16-alphaxalone;    GABA(A) receptor;    TBPS binding;    Tadpole anesthesia;   

DOI  :  10.1016/j.bmcl.2010.09.008

来源: Elsevier

【 摘 要 】

Alphaxalone, a neuroactive steroid containing a 17 beta-acetyl group, has potent anesthetic activity in humans. This pharmacological activity is attributed to this steroid's enhancement of gamma-amino butyric acid-mediated chloride currents at gamma-amino butyric acid type A receptors. The conversion of alphaxalone into Delta(16)-alphaxalone produces an analogue that lacks anesthetic activity in humans and that has greatly diminished receptor actions. By contrast, the corresponding 17 beta-carbonitrile analogue of alphaxalone and the Delta(16)-17-carbonitrile analogue both have potent anesthetic and receptor actions. The differential effect of the Delta(16)-double bond on the actions of alphaxalone and the 17 beta-carbonitrile analogue is accounted for by a differential effect on the orientation of the 17-acetyl and 17-carbonitrile substituents. (C) 2010 Elsevier Ltd. All rights reserved.

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