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GABA-steroid antagonists and their use for the treatment of cns disorders

A technology for steroids, disorders, applied in the field of preparation of said therapeutic drugs

Inactive Publication Date: 2011-01-12
UMECRINE AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the specific 3β-hydroxypregnane steroids mentioned above will inhibit GABA steroid action mainly through GABA-controlled chloride flux, and no other steroids have been found to inhibit GABA itself.

Method used

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  • GABA-steroid antagonists and their use for the treatment of cns disorders
  • GABA-steroid antagonists and their use for the treatment of cns disorders
  • GABA-steroid antagonists and their use for the treatment of cns disorders

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preparation example Construction

[0058] The preparation of the above-mentioned composition and preparation is generally well-known to those skilled in the pharmaceutical and preparation fields, and can be applied to the composition preparation of the present invention.

[0059] The inventors surprisingly revealed that a steroid with a hydrogen donor at position 3β and a hydroxyl group at position 20 can inhibit the effect of 3α-hydroxy-5α / β-steroids in vitro at a pharmaceutically suitable and practically applicable dose. , But it has a very low antagonistic effect on GABA itself. Therefore, it blocks the development of the negative effects of 3α-hydroxy-5α / β-steroids, but has the lowest effect on GABA itself. Proposed the mechanism of 3α-hydroxy-5α / β-steroids in the development of CNS disorders and 3β-hydroxy-5α / β-pregnane or 3β-sulfuric acid-5α / δ5-pregnane / pregnane steroids and 3α-hydroxy -5 The mechanism of action of the α / β-steroid interaction. Examples of this compound are shown in Table 2.

[0060] In addi...

Embodiment

[0109] The present invention is based on in vitro experiments to determine the reverse blocking effect of 3α-hydroxy-5α / β-pregnane-steroids to enhance GABA-mediated chloride ion flow and the blocking effect of GABA itself. Specificity. The results of in vitro testing of recombinant GABA-A receptors expressed on the surface of Xenopus lavies oocytes were confirmed in the cortical tissue test of male rats conducted by the inventors.

[0110] Using the voltage clamp method, the chloride ion flux in the recombinant GABA-A receptor (α1, β2, γ2L) expressed in Xenopus lavies oocytes was studied.

[0111] The GABA-A receptor used to test steroids in the present invention is recombinantly expressed in Xenopus lavies oocytes. Oocytes have a huge ability to express proteins from the mRNA injected into the oocytes to the surface membrane. The receptor contains five proteins of three different types, and mRNA of receptor subtypes α1, β2, and γ2L are expressed under the conditions of this test...

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Abstract

Compounds exhibiting 3alpha-hydroxy-5alpha / beta-steroid blocking action with no or only low antagonism against the gamma-aminobutyric acid (A) receptor (GABA-A), and compounds exhibiting partial antagonism against said receptor are presented. Methods for the prevention, treatment and / or alleviation of various CNS-disorders are suggested, as well as pharmaceutical compositions for such use.

Description

[0001] The present invention relates to the treatment, alleviation or prevention of central nervous system (CNS) disorders related to and / or induced by GABA-steroids, in particular to specific steroid compounds used for this purpose, to the use of the preparation of the therapeutic drugs, and to The method of treatment used. Background of the invention [0002] Sex hormones and stress hormone metabolites of pregnenolone, progesterone, deoxycorticosterone, cortisone, and cortisol, which are known as pregnanolone compounds; and testosterone, androstenedione, and dehydroepiandrosterone Metabolites have always been the subject of various studies, which at least to some extent explains their role in mammalian neurological signaling systems. [0003] The steroids that induce CNS symptoms and disorders that are concerned in this application all have structural similarities, containing 3α-hydroxy groups, 5α or 5β pregnane steroids, and ketone groups or hydroxyl groups at positions 17, 20 o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61P25/00A61K31/56A61K31/57
CPCA61K31/57A61K31/56A61P15/00A61P25/00A61P25/06A61P25/08A61P25/20A61P25/22A61P25/24A61P25/28A61P3/04
Inventor T·巴克斯特龙P·隆德格伦王明德
Owner UMECRINE AB