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Activity of B-nor analogues of neurosteroids on the GABA(A) receptor in primary neuronal cultures

AuthorsSuñol, Cristina ; García, Daniel A.; Bujons Vilàs, Jordi ; Krištofíková, Zdena; Matyáš, Libor; Babot, Zoila ; Kasal, Alexander
KeywordsB-Nor Analogues
3D pharmacophoric hypothesis
Issue Date9-May-2006
PublisherAmerican Chemical Society
CitationJournal of Medicinal Chemistry 49(11): 3225-3234 (2006)
AbstractA GABA(A) 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 GABA(A) 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 GABA(A) receptor.
Description10 pages, 2 tables, 7 figures.-- PMID: 16722640 [PubMed].-- Printed version published Jun 1, 2006.
Supporting information available at: http://pubs.acs.org/doi/suppl/10.1021/jm060002f
Publisher version (URL)http://dx.doi.org/10.1021/jm060002f
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