17beta-Nitro-5alpha-androstan-3alpha-ol and its 3beta-methyl derivative: neurosteroid analogs with potent anticonvulsant and anxiolytic activities.

Journal Article (Journal Article)

Many 17-substituted androstan-3alpha-ol analogs act as positive allosteric modulators of GABA(A) receptors and exert anticonvulsant and anxiolytic-like activity actions in animal models. The endogenous neurosteroid allopregnanolone (17beta-acetyl; 1) is among the most potent of these. Here we demonstrate that 3alpha-hydroxy-17beta-nitro-5alpha-androstane (2b) and its 3beta-methyl analog (3alpha-hydroxy-3beta-methyl-17beta-nitro-5alpha-androstane; 2c) modulate GABA(A) receptors as assessed by [(35)S]t-butylbicyclo-phosphorothionate and [(3)H]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 6Hz seizure models in the mouse. Furthermore, 2b exhibited anxiolytic-like activity in the elevated zero maze. The 3beta-hydroxy, 3alpha-desmethyl analog (2a) was devoid of activity on GABA(A) 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 3beta-hydroxy, 3alpha-methyl analog (2d), which is not expected to undergo epimerization. We conclude that nitro can serve as a bioisostere for acetyl at the 17beta-position of 5alpha-androstan-3alpha-ol, such that the nitro analog fully retains the bioactivity of the endogenous neurosteroid at GABA(A) receptors.

Full Text

Duke Authors

Cited Authors

  • Runyon, SP; Orr, M; Navarro, HA; Kepler, JA; Rogawski, MA; Kaminski, RM; Cook, CE

Published Date

  • September 1, 2009

Published In

Volume / Issue

  • 617 / 1-3

Start / End Page

  • 68 - 73

PubMed ID

  • 19577558

Pubmed Central ID

  • PMC5433526

Electronic International Standard Serial Number (EISSN)

  • 1879-0712

Digital Object Identifier (DOI)

  • 10.1016/j.ejphar.2009.06.052


  • eng

Conference Location

  • Netherlands