17β-Nitro-5α-androstan-3α-ol and its 3β-methyl derivative

Neurosteroid analogs with potent anticonvulsant and anxiolytic activities

Scott P. Runyon, Matthew Orr, Hernán A. Navarro, John A. Kepler, Michael A Rogawski, Rafal M. Kaminski, C. Edgar Cook

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Many 17-substituted androstan-3α-ol analogs act as positive allosteric modulators of GABAA receptors and exert anticonvulsant and anxiolytic-like activity actions in animal models. The endogenous neurosteroid allopregnanolone (17β-acetyl; 1) is among the most potent of these. Here we demonstrate that 3α-hydroxy-17β-nitro-5α-androstane (2b) and its 3β-methyl analog (3α-hydroxy-3β-methyl-17β-nitro-5α-androstane; 2c) modulate GABAA receptors as assessed by [35S]t-butylbicyclo-phosphorothionate and [3H]flunitrazepam binding with potencies equivalent to or greater than 1. These compounds also had potencies equivalent to or greater than 1 in the pentylenetetrazol and 6 Hz seizure models in the mouse. Furthermore, 2b exhibited anxiolytic-like activity in the elevated zero maze. The 3β-hydroxy, 3α-desmethyl analog (2a) was devoid of activity on GABAA receptors in vitro but had moderate activity in the seizure models, possibly as a result of epimerization in vivo at the 3-position. This conclusion was supported by the lack of in vivo activity of the 3β-hydroxy, 3α-methyl analog (2d), which is not expected to undergo epimerization. We conclude that nitro can serve as a bioisostere for acetyl at the 17β-position of 5α-androstan-3α-ol, such that the nitro analog fully retains the bioactivity of the endogenous neurosteroid at GABAA receptors.

Original languageEnglish (US)
Pages (from-to)68-73
Number of pages6
JournalEuropean Journal of Pharmacology
Volume617
Issue number1-3
DOIs
StatePublished - Sep 1 2009

Fingerprint

Anti-Anxiety Agents
GABA-A Receptors
Anticonvulsants
Neurotransmitter Agents
Seizures
Pregnanolone
Flunitrazepam
Pentylenetetrazole
Animal Models
androstan-3-ol
androstane

Keywords

  • Allopregnanolone
  • Anticonvulsant
  • Anxiolytic
  • Bioisostere
  • GABA receptor
  • Neurosteroid

ASJC Scopus subject areas

  • Pharmacology

Cite this

17β-Nitro-5α-androstan-3α-ol and its 3β-methyl derivative : Neurosteroid analogs with potent anticonvulsant and anxiolytic activities. / Runyon, Scott P.; Orr, Matthew; Navarro, Hernán A.; Kepler, John A.; Rogawski, Michael A; Kaminski, Rafal M.; Cook, C. Edgar.

In: European Journal of Pharmacology, Vol. 617, No. 1-3, 01.09.2009, p. 68-73.

Research output: Contribution to journalArticle

Runyon, Scott P. ; Orr, Matthew ; Navarro, Hernán A. ; Kepler, John A. ; Rogawski, Michael A ; Kaminski, Rafal M. ; Cook, C. Edgar. / 17β-Nitro-5α-androstan-3α-ol and its 3β-methyl derivative : Neurosteroid analogs with potent anticonvulsant and anxiolytic activities. In: European Journal of Pharmacology. 2009 ; Vol. 617, No. 1-3. pp. 68-73.
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abstract = "Many 17-substituted androstan-3α-ol analogs act as positive allosteric modulators of GABAA receptors and exert anticonvulsant and anxiolytic-like activity actions in animal models. The endogenous neurosteroid allopregnanolone (17β-acetyl; 1) is among the most potent of these. Here we demonstrate that 3α-hydroxy-17β-nitro-5α-androstane (2b) and its 3β-methyl analog (3α-hydroxy-3β-methyl-17β-nitro-5α-androstane; 2c) modulate GABAA receptors as assessed by [35S]t-butylbicyclo-phosphorothionate and [3H]flunitrazepam binding with potencies equivalent to or greater than 1. These compounds also had potencies equivalent to or greater than 1 in the pentylenetetrazol and 6 Hz seizure models in the mouse. Furthermore, 2b exhibited anxiolytic-like activity in the elevated zero maze. The 3β-hydroxy, 3α-desmethyl analog (2a) was devoid of activity on GABAA receptors in vitro but had moderate activity in the seizure models, possibly as a result of epimerization in vivo at the 3-position. This conclusion was supported by the lack of in vivo activity of the 3β-hydroxy, 3α-methyl analog (2d), which is not expected to undergo epimerization. We conclude that nitro can serve as a bioisostere for acetyl at the 17β-position of 5α-androstan-3α-ol, such that the nitro analog fully retains the bioactivity of the endogenous neurosteroid at GABAA receptors.",
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T2 - Neurosteroid analogs with potent anticonvulsant and anxiolytic activities

AU - Runyon, Scott P.

AU - Orr, Matthew

AU - Navarro, Hernán A.

AU - Kepler, John A.

AU - Rogawski, Michael A

AU - Kaminski, Rafal M.

AU - Cook, C. Edgar

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AB - Many 17-substituted androstan-3α-ol analogs act as positive allosteric modulators of GABAA receptors and exert anticonvulsant and anxiolytic-like activity actions in animal models. The endogenous neurosteroid allopregnanolone (17β-acetyl; 1) is among the most potent of these. Here we demonstrate that 3α-hydroxy-17β-nitro-5α-androstane (2b) and its 3β-methyl analog (3α-hydroxy-3β-methyl-17β-nitro-5α-androstane; 2c) modulate GABAA receptors as assessed by [35S]t-butylbicyclo-phosphorothionate and [3H]flunitrazepam binding with potencies equivalent to or greater than 1. These compounds also had potencies equivalent to or greater than 1 in the pentylenetetrazol and 6 Hz seizure models in the mouse. Furthermore, 2b exhibited anxiolytic-like activity in the elevated zero maze. The 3β-hydroxy, 3α-desmethyl analog (2a) was devoid of activity on GABAA receptors in vitro but had moderate activity in the seizure models, possibly as a result of epimerization in vivo at the 3-position. This conclusion was supported by the lack of in vivo activity of the 3β-hydroxy, 3α-methyl analog (2d), which is not expected to undergo epimerization. We conclude that nitro can serve as a bioisostere for acetyl at the 17β-position of 5α-androstan-3α-ol, such that the nitro analog fully retains the bioactivity of the endogenous neurosteroid at GABAA receptors.

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KW - Anticonvulsant

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KW - Bioisostere

KW - GABA receptor

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