Synthesis and GABAA receptor activity of 2,19-sulfamoyl analogues of allopregnanolone

DURÁN, F.J.; EDELSZTEIN, V.C.; GHINI, A.A.; REY, M.; COIRINI, H.; DAUBAN, P.H.; DODD, R.H.; BURTON, G.

BIOORGANIC & MEDICINAL CHEMISTRY.

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2009 vol. 17 p. 6526 - 6533

0968-0896

The synthesis of new analogues of allopregnanolone with a bridged sulfamidate ring over the β-face of ring A has been achieved from easily available precursors, using an intramolecular aziridination strategy. The methodology also allows the synthesis of 3α-substituted analogues such as the 3α-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 3α-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 3α-fluoro derivative was inactive in both assays.