Synthesis and GABAA receptor activity of A-homo analogues of neuroactive steroids.
A procedure is described for the preparation of A-homo-5-pregnenes via an acid catalyzed rearrangement of cyclopropylcarbinols assisted by microwave irradiation. 3alpha-Hydroxy and 4alpha-hydroxy-A-homo-5-pregnen-20-one, analogues of the neuroactive steroid allopregnanolone, were obtained by means of a regioselective epoxidation of a double bond in the expanded A-ring, using a fructose-derived chiral ketone as catalyst and oxone as oxidant. Although both these compounds were marginally active in inhibiting TBPS binding to GABA(A) receptors, 3beta-hydroxy-A-homo-5-pregnen-20-one was almost as active as allopregnanolone. Reduction of the double bond of the latter compound resulted in a ten fold loss of activity.
Dansey
María V
MV
Departamento de Química Orgánica and UMYMFOR (CONICET-FCEN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Buenos Aires, Argentina.
Di Chenna
Pablo H
PH
Veleiro
Adriana S
AS
Kristofíková
Zdena
Z
Chodounska
Hana
H
Kasal
Alexander
A
Burton
Gerardo
G
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D006878:Hydroxides / Q000737:chemistry; D008297:Male; D008872:Microwaves; D008958:Models, Molecular; D008968:Molecular Conformation; D011283:Pregnenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D006878:Hydroxides; D011283:Pregnenes; D011963:Receptors, GABA-A; C037476:tert-butylbicyclophosphorothionate; C031356:hydroxide ion