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Indole benzothiazole derivative and pharmaceutical use thereof

A kind of technology of indole benzothiazole and derivatives, applied in the field of indole benzothiazole derivatives and their pharmaceutical uses

Inactive Publication Date: 2012-03-14
FUDAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Early first-generation antischizophrenia drugs mainly treat positive symptoms, but have poor efficacy on negative symptoms, and the incidence of extrapyramidal symptoms (Extrapyramidal Symptoms, EPS) is high
The second-generation anti-schizophrenia drugs are represented by clozapine, which has a good curative effect on the positive symptoms of schizophrenia, and also improves cognitive dysfunction to a certain extent, and no obvious EPS and movement disorders will occur. In clinical use, some patients will cause severe granulocytopenia, and some even have fatal granulocytosis
Traditional receptor structure-based drug design usually only relies on the X-ray structure of the receptor or homology modeling models, but due to the flexibility of proteins in vivo, a single receptor model cannot reflect the binding of receptors to all ligands true active conformation

Method used

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  • Indole benzothiazole derivative and pharmaceutical use thereof
  • Indole benzothiazole derivative and pharmaceutical use thereof
  • Indole benzothiazole derivative and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 5-HT 1A Receptor 3D model construction

[0024] The protein sequence is from the Swiss-Prot database (http: / / www.expasy.ch / sprot / ), human epinephrine β 2 receptors and 5-HT 1A The sequence numbers of the receptors are P07550 and P08908, respectively. Using the ClustalW algorithm in the FASTA program, the 5-HT 1A receptors and adrenergic beta 2 Multiple sequence alignments were performed on the receptor sequences, and then the matched sequences were fine-tuned according to the positions of conserved residues in the GPCR superfamily. The results are shown in Table 1. 5-HT 1A receptors and adrenergic beta 2 The homology of receptor transmembrane helix is ​​41.9%.

[0025] 1 is 5-HT 1A receptors and adrenergic beta 2 Homology and similarity of the seven transmembrane domains of the receptor.

[0026] Table 1

[0027] homology similarity TM-1 25.0% 53.1% TM-2 40.4% 76.7% TM-3 52.9% 79.4% TM-4 24.0% 52.0% ...

Embodiment 2

[0029] Example 2 5-HT 1A Molecular Dynamics Simulation of Receptor Added Membrane

[0030] Molecular dynamics simulations were performed using GROMACS 3.3.1 and GROMOS96 force fields. 5-HT after initial energy optimization 1A The receptor model is inserted vertically into the POPC (palmitoyl-oleoyl-phosphatidylcholine) phospholipid bilayer. The protein and POPC structural models are dissolved in the single point charge (SPC) water molecule model; the Berendsen constant temperature method is used to maintain the system temperature at 300K; the system pressure is maintained at one atmospheric pressure; the LINCS algorithm is used to limit the bond length of all chemical bonds containing hydrogen atoms; The electrostatic interaction is calculated by the particle-mesh Ewald (PME) method, with 9 is the cut off value (cut off); the cut off value of Lennard-Jones interaction is selected as 14 . For each simulation system, a cubic box is used as the simulation unit, the prot...

Embodiment 3

[0032] Example 3 5-HT 1A Active site detection of receptors and construction of dynamic pharmacophore models.

[0033] The representative conformations of the first 10 clusters in the kinetic simulation results were taken as the receptor model, and the conserved Asp 3.32 Around 10 The in-scope regions are defined as boxes for site probing by the GRID program. Since the GPCR receptor pocket is negatively charged, four typical probes were selected: N+ (positive charge probe), O (hydrogen bond acceptor probe), N1 (hydrogen bond donor probe) and DRY (hydrophobic group probe). needles) to probe the corresponding electronegativity, hydrogen bond donor, hydrogen bond acceptor, and hydrophobic chemical environment in the protein, respectively. According to the probe points obtained by superimposing 10 conformations of Cα, an appropriate cluster was selected according to the binding energy of the GRID probe point and the nature of the interaction with the receptor amino acid res...

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Abstract

The invention, belonging to the field of biological pharmacy, relates to an indole benzothiazole derivative and an application of the derivative for preparing inhibitors of 5-HT receptor, especially an application in the field of medicines of nerve system diseases related to the 5-HT receptor. The test of bioactivity shows the indole benzothiazole derivative has inhibiting effect on the 5-HT receptor related to the pathological mechanism of nerve system diseases. The derivative can be used as a medical precursor for synthesizing the inhibitor of the 5-HT receptor, further can be used for preparing medicines for schizophrenia, parkinsonism and other nerve system diseases caused by disfunction of the 5-HT system.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, and relates to indole benzothiazole derivatives and their medicinal uses, in particular to indole benzothiazole derivatives and their use in the preparation of 5-HT receptor inhibitors, especially to indole benzothiazole derivatives and their use in the preparation of 5-HT receptor inhibitors. Benzothiazole derivatives on 5-HT 1A The affinity and action characteristics of the receptor and its application in the preparation of medicines for nervous system diseases, especially the field of medicines for nervous system diseases related to 5-HT receptors. Background technique [0002] One of the most common clinical major mental illnesses is schizophrenia, which is a persistent and chronic disease. Its clinical manifestations include positive symptoms and negative symptoms. The positive symptoms include hallucinations, delusions, chorea, etc.; Negative symptoms mainly refer to cognitive impairment...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D417/14A61K31/496A61K31/454A61P25/18A61P25/16A61P25/24
Inventor 付伟镇学初杜鹏刘慧芳沈庆
Owner FUDAN UNIV
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