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Methods for the identification of agents for the treatment of seizures, neurological diseases, endocrinopathies and hormonal diseases

A technology for neurological diseases and endocrine diseases, which can be used in the preparation methods of peptides, chemical instruments and methods, and pharmaceutical formulations, etc., and can solve problems such as adverse effects on neurotransmission

Inactive Publication Date: 2007-08-29
UCB SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, defects in synaptic vesicle function will have adverse effects on neurotransmission in general and the control of neurotransmitter release in particular
Thus, binding of levetiracetam analogues to LBS is expected to result in modification of the function of LBS protein components in the brain, leading to the desired therapeutic outcome of anticonvulsant activity

Method used

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  • Methods for the identification of agents for the treatment of seizures, neurological diseases, endocrinopathies and hormonal diseases
  • Methods for the identification of agents for the treatment of seizures, neurological diseases, endocrinopathies and hormonal diseases
  • Methods for the identification of agents for the treatment of seizures, neurological diseases, endocrinopathies and hormonal diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0198] Example 1. Development of Levetiracetam Analogs for Binding Studies

[0199] LEV binding has been shown to be preferentially localized to specific binding sites in the brain (levetiracetam binding site or LBS: Noyer et al., Euro. J. Pharmacol. 286:137-146. (1995); Gillard et al. 2003)). However,[ 3 H]LEV exhibits only micromolar affinity for this site, making it unsuitable for in-depth characterization. This example describes the [ 3 H]ucb 30889, a conjugate of (2S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide, an analogue of levetiracetam nature. Binding experiments were performed on crude rat meninges at 4°C as described by Noyer et al. (Euro. J. Pharmacol. 286:137-146 (1995)). The incubation time used for the equilibrium study was 120 minutes. For kinetic and competition studies, use a solution containing 2mM Mg 2+ [ 3 H]ucb 30889 (30Ci / mmol). Localization of LBS in brain substructures was assessed by autoradiography of 25 μm thick sections incubated ...

Embodiment 2

[0206] Example 2. Cellular and subcellular distribution of LBS

[0207] For in situ identification and characterization of LBS, the [ 3 H]ucb 30889 maps LBS in the brain and studies its cellular and subcellular distribution. For rat brain autoradiography, 25 μm sections were treated with 1.3 nM [ 3 H]ucb 30889 was incubated in 50 mM Tris-HCl buffer (pH 7.4) at 4°C for 120 minutes. Binding assays for rat meninges as well as various neuronal cell lines were performed under similar conditions. Non-specific binding was determined by including 1 mM levetiracetam in the assay. For photolabeling, the membrane was treated with 40 nM [ 3 H]ucb 30889 was incubated in the same buffer at 4° C. for 120 minutes, followed by 30 minutes of UV light irradiation (Fuks et al., Eur. J. Pharmacol. 478: 11-19 (2003)).

[0208] For rat brain autoradiography, 25 μm sections were treated with 1.3 nM [ 3H]ucb 30889 was incubated in 50 mM Tris-HCl buffer (pH 7.4) at 4°C for 120 minutes. Figure 7 ...

Embodiment 3

[0218] Example 3. LBS over SV2A

[0219] In this example, biochemical characterization of LBS in rat brain led to studies identifying potential candidate LBS proteins for cloning and binding characterization. The SV2 protein family was analyzed as candidates for targeting LBS based on the membrane-integrated nature of the proteins, brain-specific expression, apparent size, and synaptic vesicle localization. Accordingly, the SV2 protein was cloned and assayed for LBS ligand binding.

[0220] Material:

[0221] Levetiracetam and derivatives were synthesized at UCB Pharma (Braine-I'Alleud, Belgium). [ 3 H]ucb 30889, (2S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide (32 Ci / mmol) was purchased from Amersham Biosciences (Roosendaal, The Netherlands) custom markings. The monoclonal antibody against the SV2 protein developed by Buckley and Kelly (Buckley et al., J.Cell.Biol., 100, 1284-94 (1985)) was developed from NICHD and sponsored by University of Iowa, Department of ...

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Abstract

The present invention is drawn to methods of characterization of the properties and functions of SV2 proteins. The invention further includes methods of identifying compounds or agents which modulate the activity of SV2 proteins. Included in these methods is the identification of compounds or agents which modulate the binding of levetiracetam to SV2 proteins, including SV2A. Additionally, the present invention provides biotinylated ligands as a tool to screen chemical libraries and characterize the SV2 proteins. Further, the present invention provides a method of solubilizing and purifying functionally active membrane associated proteins, such as SV2.

Description

[0001] related application [0002] This application claims the benefit of US Provisional Application 60 / 506,764, filed September 30, 2003, and US Provisional Application 60 / 430,372, filed December 3, 2002, which are hereby incorporated by reference in their entirety. field of invention [0003] The present invention relates generally to the field of drug discovery for neurological, endocrine and hormonal diseases. Background of the invention [0004] Neurological diseases afflict large numbers of individuals and pose an increasing economic challenge to health care systems because their causes are poorly understood, their diagnosis is often subjective and most lack effective treatment. In general, brain activity is fundamentally determined by the ability of neurons to communicate at synaptic connections. Specific neurotransmitter chemicals are packaged in presynaptic neurons into synaptic vesicles that fuse with the presynaptic membrane to release quantitative amounts of ne...

Claims

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Application Information

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IPC IPC(8): A61K31/00G01N33/50G01N33/68G01N33/577C07K14/00C07K1/14C07H21/04
Inventor B·林奇K·诺卡B·福克斯
Owner UCB SA
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