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

0458613 - ÚOCHB 2017 RIV US eng J - Journal Article
Kasal, Alexander - Buděšínský, Miloš - Mareš, Pavel - Krištofíková, Z. - Leitao, A. J. - Sá e Melo, M. L. - Silva, M. M. C.
Neurosteroids: Can a 2alpha,3alpha-epoxy ring make up for the 3alpha-hydroxyl group?
Steroids. Roč. 105, Jan (2016), s. 12-18. ISSN 0039-128X. E-ISSN 1878-5867
R&D Projects: GA ČR(CZ) GA305/09/0846; GA ČR(CZ) GBP304/12/G069
Institutional support: RVO:61388963 ; RVO:67985823
Keywords : neurosteroids * NMR spectrometry * GABA(A) receptor * TBPS-test
Subject RIV: CC - Organic Chemistry; FH - Neurology (FGU-C)
Impact factor: 2.282, year: 2016

Seven steroid epoxides were prepared from 5 alpha-pregn-2-en-20-one and 5 alpha-pregn-3-en-20-one and their side-chain derivatives. All compounds were tested in vitro for binding to gamma-aminobutyric acid (GABA(A)) receptor, some of them also in vivo for anticonvulsant action. 2 alpha,3 alpha-Epoxy-5 alpha-pregnan-20-one inhibited the TBPS binding to the GABA(A) receptor and showed a moderate anticonvulsant action in immature rats. In contrast, its 3 alpha,4 alpha-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 2 alpha,3 alpha-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 3 alpha-hydroxyl group is known to be essential for the GABA(A) 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 2 alpha,3 alpha-epoxy ring is another structural pattern with ability to bind the GABA(A)R.
Permanent Link: http://hdl.handle.net/11104/0258860