Synthesis and GABA(A) receptor activity of 2,19-sulfamoyl analogues of allopregnanolone

Bioorg Med Chem. 2009 Sep 15;17(18):6526-33. doi: 10.1016/j.bmc.2009.08.008. Epub 2009 Aug 9.

Abstract

The synthesis of new analogues of allopregnanolone with a bridged sulfamidate ring over the beta-face of ring A has been achieved from easily available precursors, using an intramolecular aziridination strategy. The methodology also allows the synthesis of 3alpha-substituted analogues such as the 3alpha-fluoro derivative. GABA(A) receptor activity of the synthetic analogues was evaluated by assaying their effect on the binding of [(3)H]flunitrazepam and [(3)H]muscimol. The 3alpha-hydroxy-2,19-sulfamoyl analogue and its N-benzyl derivative were more active than allopregnanolone for stimulating binding of [(3)H]flunitrazepam. For the binding of [(3)H]muscimol, both synthetic analogues and allopregnanolone stimulated binding to a similar extent, with the N-benzyl derivative exhibiting a higher EC(50). The 3alpha-fluoro derivative was inactive in both assays.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / metabolism
  • Cerebellum / metabolism
  • Male
  • Models, Molecular
  • Pregnanolone / analogs & derivatives*
  • Pregnanolone / chemical synthesis
  • Pregnanolone / pharmacology*
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / metabolism*
  • Structure-Activity Relationship
  • Sulfonamides / chemistry

Substances

  • Receptors, GABA-A
  • Sulfonamides
  • Pregnanolone