Neurosteroid analogues: synthesis of 6-aza-allopregnanolone |
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Authors: | Alexander Kasal Libor Matyáš Miloš Buděšínský |
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Institution: | Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, CZ166 10 Prague 6, Czech Republic |
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Abstract: | An efficient synthesis of 6-azapregnane derivatives and their biological activity is described. The nitrogen was introduced into the B ring using Beckmann rearrangement of the (E)-oxime of 6-oxo-B-nor-5α-pregnane derivatives. The required 3α-hydroxyl was produced either by solvolysis of the corresponding 3β-mesyloxy group or by the Meerwein-Ponndorf-Verley reduction of the 3-oxo group; this reduction could be carried out selectively with an unprotected 3,20-dioxo derivative. The binding of the 6-aza-steroids to the γ-aminobutyric acid receptor (GABAA) was measured using 35S]-tert-butyl-bicyclo2.2.2]phosphorothionate (TBPS) and 3H]flunitrazepam. The only analogue to be slightly active was that lacking any oxygen function in position 3. |
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Keywords: | 6-Azasteroids Beckmann rearrangement Henbest reaction Conformation of oximes GABAA receptor NMR spectroscopy |
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