title: Synthesis and GABA(A) receptor activity of 2,19-sulfamoyl analogues of allopregnanolone.
abstract: The synthesis of new analogues of allopregnanolone with a bridged sulfamidate ring over the beta-face of ring A has been achieved from easily available precursors, using an intramolecular aziridination strategy. The methodology also allows the synthesis of 3alpha-substituted analogues such as the 3alpha-fluoro derivative. GABA(A) receptor activity of the synthetic analogues was evaluated by assaying their effect on the binding of [(3)H]flunitrazepam and [(3)H]muscimol. The 3alpha-hydroxy-2,19-sulfamoyl analogue and its N-benzyl derivative were more active than allopregnanolone for stimulating binding of [(3)H]flunitrazepam. For the binding of [(3)H]muscimol, both synthetic analogues and allopregnanolone stimulated binding to a similar extent, with the N-benzyl derivative exhibiting a higher EC(50). The 3alpha-fluoro derivative was inactive in both assays.
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Durán
authors.forename: Valeria C
authors.initials: VC
authors.lastname: Edelsztein
authors.forename: Alberto A
authors.initials: AA
authors.lastname: Ghini
authors.forename: Mariana
authors.initials: M
authors.lastname: Rey
authors.forename: Héctor
authors.initials: H
authors.lastname: Coirini
authors.forename: Philippe
authors.initials: P
authors.lastname: Dauban
authors.forename: Robert H
authors.initials: RH
authors.lastname: Dodd
authors.forename: Gerardo
authors.initials: G
authors.lastname: Burton
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D011963:Receptors, GABA-A; D013449:Sulfonamides; D011280:Pregnanolone