Allopregnanolone and pregnanolone analogues modified in the C ring: Synthesis and activity

El pdf es la versión post-print.(25R)-3β-Hydroxy-5α-spirostan-12-one (hecogenin) and 11α-hydroxypregn-4-ene-3,20-dione (11α-hydroxyprogesterone) were used as starting materials for the synthesis of a series of 11- and 12-substituted derivatives of 5ξ-pregnanolone (3α-hydroxy-5α- pregnan-20-one and 3α-hydroxy-5β-pregnan-20-one), the principal neurosteroid acting via γ-aminobutyric acid (GABA). These analogues were designed to study the structural requirements of the corresponding GABA A receptor. Their biological activity was measured by in vitro test with [3H]flunitrazepam as radioligand in which allopregnanolone and its active analogues stimulated the binding to the GABAA receptor. Analysis of the SAR data suggests dependence of the flunitrazepam binding activity on the hydrophobic-hydrophilic balance of the groups at the C-ring edge rather than on specific interactions between them and the receptor. © 2013 American Chemical Society.This work was supported by Czech Grant 303/12/1464, Research Project of the AS CR RVO 61388963, and the Spanish Grants PI 061212 and PI 10/0453 from the Ministries of Health and of Science and Innovation, Grant 2009/SGR/214 from the Generalitat of Catalunya, and Grant 2006CZ0025 from CSIC.Peer Reviewe