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

Abstract：

:A GABA(A) receptor study of several B-nor analogues of allopregnanolone and pregnanolone has been carried out. B-norallopregnanolone (i.e., 3alpha-hydroxy-7-nor-5alpha-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 3alpha-hydroxy-7-nor-5xi-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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Suñol C,García DA,Bujons J,Kristofíková Z,Matyás L,Babot Z,Kasal A

doi

10.1021/jm060002f

subject

Has Abstract

pub_date

2006-06-01 00:00:00

pages

3225-34

issue

11

eissn

0022-2623

issn

1520-4804

journal_volume

49

pub_type

杂志文章

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