title: Neurosteroid analogues. 15. A comparative study of the anesthetic and GABAergic actions of alphaxalone, Δ16-alphaxalone and their corresponding 17-carbonitrile analogues.
abstract: 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.
authors.affiliation: Department of Developmental Biology, Campus Box 8103, Washington University in St. Louis, School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Achintya K
authors.initials: AK
authors.lastname: Bandyopadhyaya
authors.forename: Brad D
authors.initials: BD
authors.lastname: Manion
authors.forename: Ann
authors.initials: A
authors.lastname: Benz
authors.forename: Amanda
authors.initials: A
authors.lastname: Taylor
authors.forename: Nigam P
authors.initials: NP
authors.lastname: Rath
authors.forename: Alex S
authors.initials: AS
authors.lastname: Evers
authors.forename: Charles F
authors.initials: CF
authors.lastname: Zorumski
authors.forename: Steven
authors.initials: S
authors.lastname: Mennerick
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Covey
mesh_terms: D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry*; D011277:Pregnanediones / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013055:Spectrophotometry, Infrared; D005680:gamma-Aminobutyric Acid / Q000187:drug effects*
chemical_list: D000777:Anesthetics; D009570:Nitriles; D011277:Pregnanediones; D005680:gamma-Aminobutyric Acid; C006477:alphaxalone