Synthesis and GABAA receptor activity of A-homo analogues of neuroactive steroids

A procedure is described for the preparation of A-homo-5-pregnenes via an acid catalyzed rearrangement of cyclopropylcarbinols assisted by microwave irradiation. 3α-Hydroxy and 4α-hydroxy-A-homo-5-pregnen-20-one, analogues of the neuroactive steroid allopregnanolone, were obtained by means of a regioselective epoxidation of a double bond in the expanded A-ring, using a fructose-derived chiral ketone as catalyst and oxone as oxidant. Although both these compounds were marginally active in inhibiting TBPS binding to GABAA receptors, 3β-hydroxy-A-homo-5-pregnen-20-one was almost as active as allopregnanolone. Reduction of the double bond of the latter compound resulted in a ten fold loss of activity.

Graphical abstractA-homo steroids were synthesized by acid catalyzed rearrangement of a cyclopropylpregnane. The unsaturated 3b-hydroxy steroid was as active as allopregnanolone in the inhibition of TBPS binding to GABAA receptors.Figure optionsDownload full-size imageDownload as PowerPoint slide