Synthesis and GABAAreceptor activity of A-homo analogues of neuroactive steroids

María V. Dansey, Pablo H. Di Chenna, Adriana S. Veleiro, Zdena Krištofíková, Hana Chodounska, Alexander Kasal, Gerardo Burton, María V. Dansey, Pablo H. Di Chenna, Adriana S. Veleiro, Zdena Krištofíková, Hana Chodounska, Alexander Kasal, Gerardo Burton

Index: Eur. J. Med. Chem. 45 , 3063-9, (2010)

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Abstract

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 GABA A 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.