Synthesis and GABAA Receptor Activity of 2,19-Sulfamoyl Analogues of Allopregnanolone

FERNANDO J. DURÁN; VALERIA C. EDELSZTEIN; ALBERTO A. GHINI; MARIANA REY; HÉCTOR COIRINI; PHILIPPE DAUBAN; ROBERT H. DODD; GERARDO BURTON

BIOORGANIC & MEDICINAL CHEMISTRY.

Elsevier

Año: 2009 vol. 17 p. 6526 - 6533

0968-0896

The synthesis of new analogues of allopregnanolone with a bridged sulfamidate ring over the â-face of ring A has been achieved from easily available precursors, using an intramolecular aziridination strategy. The methodology also allows the synthesis of 3á-substituted analogues such as the 3á-fluoro derivative. GABAA receptor activity of the synthetic analogues was evaluated by assaying their effect on the binding of [3H]flunitrazepam and [3H]muscimol. The 3á-hydroxy-2,19-sulfamoyl analogue and its N-benzyl derivative were more active than allopregnanolone for stimulating binding of [3H]flunitrazepam. For the binding of [3H]muscimol, both synthetic analogues and allopregnanolone stimulated binding to a similar extent, with the N-benzyl derivative exhibiting a higher EC50. The 3á-fluoro derivative was inactive in both assays.