Neurosteroids: Can a 2alpha,3alpha-epoxy ring make up for the 3alpha-hydroxyl group?

• 2α,3α-epoxy-5α-pregnan-20-one lacks the 3α-hydroxyl.
• Still it binds GABAAR receptor 2α,3α-epoxides 4 and 7 exhibit moderate dose-dependent action in 12 day old rats.
• The above GABAA-like activity is reduced in more polar analogues.

Seven steroid epoxides were prepared from 5α-pregn-2-en-20-one and 5α-pregn-3-en-20-one and their side-chain derivatives. All compounds were tested in vitro for binding to γ-aminobutyric acid (GABAA) receptor, some of them also in vivo for anticonvulsant action.2α,3α-Epoxy-5α-pregnan-20-one inhibited the TBPS binding to the GABAA receptor and showed a moderate anticonvulsant action in immature rats. In contrast, its 3α,4α-isomer was inactive. More polar epoxide derivatives, modified at the side chain were less active or inactive.Noteworthy, diol 20, the product of trans-diaxial opening of the 2α,3α-epoxide 4, was not able to inhibit the TBPS binding, showing that the activity of the epoxide is due to the compound itself and not to its hydrolytic product.The 3α-hydroxyl group is known to be essential for the GABAA receptor binding. Despite the shortness of in vivo effects which are probably due to metabolic inactivation of the products prepared, our results show that the 2α,3α-epoxy ring is another structural pattern with ability to bind the GABAAR.

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