title: Neurosteroids: Can a 2alpha,3alpha-epoxy ring make up for the 3alpha-hydroxyl group?
abstract: 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.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences, Prague CZ16610, Czech Republic. Electronic address: Kasal@uochb.cas.cz.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kasal
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences, Prague CZ16610, Czech Republic.
authors.forename: Miloš
authors.initials: M
authors.lastname: Buděšínský
authors.affiliation: Institute of Physiology, Academy of Sciences, CZ14220 Prague 4, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Mareš
authors.affiliation: Alzheimer's Disease Center, National Institute of Mental Health, Klecany CZ25067, Czech Republic.
authors.forename: Zdena
authors.initials: Z
authors.lastname: Krištofíková
authors.affiliation: Faculdade de Farmácia, Universidade de Coimbra, 3000-508 Coimbra, Portugal; CNC - Centre for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Alcino J
authors.initials: AJ
authors.lastname: Leitão
authors.affiliation: Faculdade de Farmácia, Universidade de Coimbra, 3000-508 Coimbra, Portugal; CNC - Centre for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Sá e Melo
authors.affiliation: Faculdade de Farmácia, Universidade de Coimbra, 3000-508 Coimbra, Portugal; CNC - Centre for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Maria Manuel C
authors.initials: MM
authors.lastname: Silva
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D006900:Hydroxylation; D008297:Male; D018377:Neurotransmitter Agents / Q000138:chemical synthesis / Q000737:chemistry*; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D004852:Epoxy Compounds; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A
keywords: Epileptic seizures; Epoxidation; GABA(A) receptor; NMR spectrometry; Neurosteroids; Pentylenetetrazol (PTZ) model; TBPS-test