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

Achintya K. Bandyopadhyaya; Brad D. Manion; Ann Benz; Amanda Taylor; Nigam P. Rath; Alex S. Evers; Charles F. Zorumski; Steven Mennerick; Douglas F. Covey

doi:10.1016/j.bmcl.2010.09.008

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

Achintya K. Bandyopadhyaya, Brad D. Manion, Ann Benz, Amanda Taylor, Nigam P. Rath, Alex S. Evers, Charles F. Zorumski, Steven Mennerick, Douglas F. Covey

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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 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.

Original language	English
Pages (from-to)	6680-6684
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	22
DOIs	https://doi.org/10.1016/j.bmcl.2010.09.008
State	Published - Nov 15 2010

Keywords

Alphaxalone
Anesthetic steroid
Delta-16-alphaxalone
GABA receptor
TBPS binding
Tadpole anesthesia

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10.1016/j.bmcl.2010.09.008

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Bandyopadhyaya, A. K., Manion, B. D., Benz, A., Taylor, A., Rath, N. P., Evers, A. S., Zorumski, C. F., Mennerick, S., & Covey, D. F. (2010). Neurosteroid analogues. 15. A comparative study of the anesthetic and GABAergic actions of alphaxalone, Δ¹⁶-alphaxalone and their corresponding 17-carbonitrile analogues. Bioorganic and Medicinal Chemistry Letters, 20(22), 6680-6684. https://doi.org/10.1016/j.bmcl.2010.09.008

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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 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.",

keywords = "Alphaxalone, Anesthetic steroid, Delta-16-alphaxalone, GABA receptor, TBPS binding, Tadpole anesthesia",

author = "Bandyopadhyaya, {Achintya K.} and Manion, {Brad D.} and Ann Benz and Amanda Taylor and Rath, {Nigam P.} and Evers, {Alex S.} and Zorumski, {Charles F.} and Steven Mennerick and Covey, {Douglas F.}",

note = "Funding Information: This work was supported by NIH Grant GM47969 (D.F.C., A.S.E., C.F.Z.) and the Bantly Foundation. X-ray crystal structures were made possible by NSF Shared Instrument Grant No. CHE-042097. ",

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doi = "10.1016/j.bmcl.2010.09.008",

language = "English",

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Bandyopadhyaya, AK, Manion, BD, Benz, A, Taylor, A, Rath, NP, Evers, AS , Zorumski, CF , Mennerick, S & Covey, DF 2010, 'Neurosteroid analogues. 15. A comparative study of the anesthetic and GABAergic actions of alphaxalone, Δ¹⁶-alphaxalone and their corresponding 17-carbonitrile analogues', Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 22, pp. 6680-6684. https://doi.org/10.1016/j.bmcl.2010.09.008

Neurosteroid analogues. 15. A comparative study of the anesthetic and GABAergic actions of alphaxalone, Δ¹⁶-alphaxalone and their corresponding 17-carbonitrile analogues. / Bandyopadhyaya, Achintya K.; Manion, Brad D.; Benz, Ann et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 20, No. 22, 15.11.2010, p. 6680-6684.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Neurosteroid analogues. 15. A comparative study of the anesthetic and GABAergic actions of alphaxalone, Δ16-alphaxalone and their corresponding 17-carbonitrile analogues

AU - Bandyopadhyaya, Achintya K.

AU - Manion, Brad D.

AU - Benz, Ann

AU - Taylor, Amanda

AU - Rath, Nigam P.

AU - Evers, Alex S.

AU - Zorumski, Charles F.

AU - Mennerick, Steven

AU - Covey, Douglas F.

N1 - Funding Information: This work was supported by NIH Grant GM47969 (D.F.C., A.S.E., C.F.Z.) and the Bantly Foundation. X-ray crystal structures were made possible by NSF Shared Instrument Grant No. CHE-042097.

PY - 2010/11/15

Y1 - 2010/11/15

N2 - 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.

AB - 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.

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KW - Anesthetic steroid

KW - Delta-16-alphaxalone

KW - GABA receptor

KW - TBPS binding

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M3 - Article

C2 - 20875742

AN - SCOPUS:77958049931

SN - 0960-894X

VL - 20

SP - 6680

EP - 6684

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 22

ER -

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

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