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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: 2007-11-21
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

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preparation example Construction

[0055] The preparation of the above-mentioned compositions and formulations is generally well known to those skilled in the field of pharmacy and formulation, and can be applied to the formulation of the compositions of the present invention.

[0056] The present inventors have surprisingly revealed that steroids having a hydrogen donor at the 3β position and a hydroxyl group at the 20 position can inhibit the action of 3α-hydroxy-5α / β-steroids in vitro at pharmaceutically acceptable and practical doses , but has a very low antagonistic effect on the action of GABA itself. It therefore blocks the development of the negative effects of 3α-hydroxy-5α / β-steroids, but has a minimal effect on GABA's own action. Proposed mechanistic role of 3α-hydroxy-5α / β-steroids in the development of CNS disorders and 3β-hydroxy-5α / β-pregnane or 3β-sulfate-5α / δ5-pregnane / pregnene steroids with 3α-hydroxy - Mechanism of action of 5α / β-steroid interactions. Examples of such compounds are shown in...

Embodiment

[0106] The present invention is based on in vitro experiments to determine the reverse blocking effect on 3α-hydroxyl-5α / β-pregnane-steroid-enhanced GABA-mediated chloride flow, and the blocking effect on GABA itself. specificity. The results of the in vitro test of the recombinant GABA-A receptor expressed on the surface of Xenopus lavies oocytes were confirmed in the test of male rat cortical tissue conducted by the present inventors.

[0107] Chloride flux in recombinant GABA-A receptors (α1, β2, γ2L) expressed in Xenopus lavies oocytes was studied using the voltage-clamp method.

[0108] The GABA-A receptor used for testing steroids in the present invention was recombinantly expressed in Xenopus lavies oocytes. Oocytes have a tremendous capacity for surface membrane expression of proteins from mRNA injected into the oocyte. The receptor contains five proteins of three different types, and the mRNAs for receptor subtypes α1, β2, γ2L are expressed under the conditions 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, mitigation or prevention of central nervous system (CNS) disorders associated and / or induced by GABA-steroids, in particular to specific steroid compounds for this purpose, to the use for the preparation of said therapeutic medicaments, and to The treatments it uses. Background of the invention [0002] Sex and stress hormone metabolites of pregnenolone, progesterone, deoxycorticosterone, cortisone, and cortisol, known pregnenolone compounds; and testosterone, androstenedione, and dehydroepiandrosterone Metabolites have been the subject of various studies, at least in part, to account for their role in mammalian neurological signaling. [0003] The steroids that induce CNS symptoms and disorders of interest in this application all share a structural similarity, containing a 3α-hydroxyl group, a 5α or 5β pregnane steroid body, and a keto or hydroxyl group at position 17, 20, or 21 group. [0004] Steroids containing 3α-hy...

Claims

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Application Information

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