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

• Published in: Bioorganic & medicinal chemistry letters 2010-11, Vol.20 (22), p.6680-6684
• Main Authors: Bandyopadhyaya, Achintya K., Manion, Brad D., Benz, Ann, Taylor, Amanda, Rath, Nigam P., Evers, Alex S., Zorumski, Charles F., Mennerick, Steven, Covey, Douglas F.
• Format: Article
• Language: English
• Subjects: Alphaxalone; Anesthetic steroid; Anesthetics - pharmacology; Anesthetics. Neuromuscular blocking agents; Animals; Biological and medical sciences; Crystallography, X-Ray; Delta-16-alphaxalone; GABAA receptor; Gabaergic and benzodiazepinic system; gamma-Aminobutyric Acid - drug effects; Magnetic Resonance Spectroscopy; Medical sciences; Models, Molecular; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Nitriles - chemistry; Pharmacology. Drug treatments; Pregnanediones - chemistry; Pregnanediones - pharmacology; Rats; Spectrophotometry, Infrared; Tadpole anesthesia; TBPS binding
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.09.008

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 Δ16-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 Δ16-17-carbonitrile analogue both have potent anesthetic and receptor actions. The differential effect of the Δ16-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.