Neurosteroid Analogues. 13. Synthetic methods for the preparation of 2beta-hydroxygonane derivatives as structural mimics of ent-3alpha-hydroxysteroid modulators of GABA(A) receptors.

Many different 3alpha-hydroxysteroids in the androstane and pregnane steroid series enhance the actions of gamma-aminobutyric acid (GABA) at GABA type-A (GABA(A)) receptors in the mammalian central nervous system. Recent studies have shown that (3alpha,5alpha)-3-hydroxyandrostan-17-one (androsterone) is less active at these receptors than its enantiomer ent-androsterone. Further structure-activity relationship (SAR) studies are needed to explore the structural features of ent-androsterone that are important for its enhanced action at these receptors. Molecular modeling shows that 2beta-hydroxysteroids are similar in three-dimensional shape to the enantiomers of 3alpha-hydroxysteroids. The development of synthtetic methods to gain access to C(17)-substituted analogues of 2beta-hydroxygonanes for SAR studies is demonstrated with the synthesis of (2beta,5alpha,13beta,14beta)-2-hydroxygonan-17-one.