Synthesis and GABA(A) receptor activity of 6-oxa-analogs of neurosteroids

The 6-oxasteroids 3 alpha-hydroxy-6-oxa-5 alpha-pregnan-20-one (3) and 3 al pha-hydroxy-6-oxa-5 beta-pregnan-20-one (4) were obtained from pregnenolone acetate via the corresponding (5 alpha or 5 beta) 3 beta,20 beta-diacetoxy -6-oxa-pregnane. Both steroids showed ca. 100-fold reduced potency for modu lating [H-3]flunitrazepam, [H-3]muscimol or [S-35]TBPS binding to the GABA( A) receptor when compared to their natural carbon analogs 3 alpha-hydroxy-5 alpha-pregnan-20-one (1) and 3 alpha-hydroxy-5 beta-pregnan-20-one (2). (C ) 2000 Elsevier Science Inc. All rights reserved.