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.; DODD, R.H.; BURTON, G.

BIOORGANIC & MEDICINAL CHEMISTRY.

Elsevier

Año: 2009 vol. 17 p. 6526 - 6533

0968-0896

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman";} @page Section1 {size:612.0pt 792.0pt; margin:72.0pt 90.0pt 72.0pt 90.0pt; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1The synthesis of new analogues of allopregnanolone with a bridged sulfamidate ring over the b-face of ring A has been achieved from easily available precursors, using an intramolecular aziridination strategy. The methodology also allows the synthesis of 3a-substituted analogues such as the 3a-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 3a-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 3a-fluoro derivative was inactive in both assays.