Activity of B-nor analogues of neurosteroids on the GABAA receptor in primary neuronal cultures

Authors
Suñol, Cristina; Garcia, Daniel Asmed; Bujons, Jordi; Kristofikova, Zdena; Matyas, Libor; Babot, Zoila; Kasal, Alexander
Publication Year
2006
Language
English
Format
article
Status
Published version
Description
A GABAA receptor study of several B-nor analogues of allopregnanolone and pregnanolone has been carried out. B-Norallopregnanolone (i.e., 3α-hydroxy-7-nor-5α-pregnan-20-one) was found comparable to allopregnanolone when measured with labeled TBPS. Analogous results were obtained from their effect on neurons in culture: this time, both 3α-hydroxy-7-nor-5ξ-pregnan-20-ones (5 and 6) were found to stimulate [3H]flunitrazepam binding and GABA-induced 36Cl - influx. These effects were inhibited by GABAA receptor antagonists. Other analogues carrying electronegative substituents (epoxides 9 and 10 and ketone 12) in the B ring were inactive. Similarly, B-normal ketones 17, and 18 and 6-azasteroids 20 and 21 were also inactive. B-Nor analogues 5 and 6 did not induce neurotoxicity at relevant concentrations. A computational analysis of active and inactive neurosteroid analogues allowed the proposal of a 3D pharmacophoric hypothesis of their interaction with the GABAA receptor. © 2006 American Chemical Society.
Fil: Suñol, Cristina. Consejo Superior de Investigaciones Científicas; España
Fil: Garcia, Daniel Asmed. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Superior de Investigaciones Científicas; España
Fil: Bujons, Jordi. Consejo Superior de Investigaciones Científicas; España
Fil: Kristofikova, Zdena. Academy of Sciences of the Czech Republic; República Checa
Fil: Matyas, Libor. Academy of Sciences of the Czech Republic; República Checa
Fil: Babot, Zoila. Consejo Superior de Investigaciones Científicas; España
Fil: Kasal, Alexander. Academy of Sciences of the Czech Republic; República Checa
Subject
Neurosteroids
GABAA receptor
Pharmacophore model
Receptor binding and chloride flux
Otras Ciencias Biológicas
Ciencias Biológicas
CIENCIAS NATURALES Y EXACTAS
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/55491