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The medicinal use of 4-(4-phenylpiperazinyl)quinazoline derivatives

A use, the technology of BAS04932482, applied in the field of biopharmaceuticals, can solve the problems of unclear pathogenesis, complicated pathogenesis of schizophrenia, etc.

Inactive Publication Date: 2016-03-30
FUDAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Studies have shown that the pathogenesis of schizophrenia is relatively complex, involving genetic factors, personality factors, psychological factors, environmental factors and body physiological factors, etc. Genetic factors play an important role in the pathogenesis of schizophrenia, but its pathogenesis is still unclear

Method used

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  • The medicinal use of 4-(4-phenylpiperazinyl)quinazoline derivatives
  • The medicinal use of 4-(4-phenylpiperazinyl)quinazoline derivatives
  • The medicinal use of 4-(4-phenylpiperazinyl)quinazoline derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1 Dopamine D 3 Receptor 3D structure optimization

[0025] Dopamine D 3 Receptor (EllenY.T.Chien, WeiLiu, QiangZhao, VsevolodKatritch, GyeWonHan, MichaelA.Hanson, LeiShi, AmyHauckNewman, JonathanA.Javitch, VadimCherezov, RaymondC.Stevens.Science330, (2010) 1091-1095.PDB No. 3PBL) Energy optimization, excluding unreasonable structures in the acceptor, thus obtaining the figure 1 Optimized D shown 3 The three-dimensional structure of the receptor.

Embodiment 2

[0026] Embodiment 2 dopamine D 3 Active site detection of receptors and construction of pharmacophore models.

[0027] Dopamine D 3 The region within 10 ? of the conserved Asp3.32 in the receptor structure was defined as a box 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 binding energy between the GRID probe and the active pocket of the receptor and the nature of the interaction with the amino acid residues, an appropriate cluster is selected, and the geometric center and radius of rotation of the cluster are calculated.

[0028] Use the Catalyst module of DiscoveryStudio to build a p...

Embodiment 3

[0029] Example 3 Virtual Screening and Biological Activity Test Based on Receptor Pharmacophore Model

[0030]Use the bestflexible method of the Catalyst module of the DiscoveryStudio program to search the MayBridge database (containing 61602 compounds), according to the matching value (FitValue) of the small molecule and the pharmacophore, the docking of the small molecule and the receptor, the G-Score scoring function, and the small molecule ADMET As a result of property prediction, 7 candidate compounds were selected from the ASINEX small molecule database (http: / / www.asinex.com), purchased from ASINEX Company in the Netherlands and tested for activity.

[0031] dopamine D 3 The receptor positive control substance was Spiperone, and both the test drug and the positive drug were dissolved in DMSO to 0.01 mol / L, and then diluted to 100 μmol / L with deionized water. Add 10 μL of the test compound and radioligand and 80 μL of the receptor protein into the reaction test tube so ...

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Abstract

The invention belongs to the field of biopharmaceuticals, and relates to the medicinal use of 4-(4-phenylpiperazinyl)quinazoline derivatives, in particular to the use of 4-(4-phenylpiperazinyl)quinazoline derivatives in The use in the preparation of medicines for treating nervous system diseases, especially the use of 4-(4-phenylpiperazinyl) quinazoline derivatives in the preparation of dopamine D3 receptor inhibitors. The present invention has undergone biological activity test experiments, and the results show that the 4-(4-phenylpiperazinyl)quinazoline derivatives have a good inhibitory effect on D3 receptors, and the compounds involved in the present invention can be used as drugs The lead compound is synthesized as a dopamine D3 receptor inhibitor, which is further used to prepare drugs for treating schizophrenia and Parkinson's disease caused by dopamine system dysfunction.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, and relates to the medicinal use of 4-(4-phenylpiperazinyl)quinazoline derivatives, in particular to the use of 4-(4-phenylpiperazinyl)quinazoline derivatives in The use in the preparation of drugs for the treatment of nervous system diseases, especially related to the use of 4-(4-phenylpiperazinyl)quinazoline derivatives in the preparation of dopamine D 3 Use in receptor inhibitors. Background technique [0002] Schizophrenia (schizophrenia) is the most common clinical persistent and chronic major mental illness. Its clinical manifestations are positive symptoms and negative symptoms. The former includes hallucinations, delusions, chorea, etc.; the latter mainly refers to cognitive impairment , learning and memory impairment, working memory impairment, etc. With the continuous increase of people's work and life pressure, mental problems have serious adverse effects on the whole society. Stud...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/95A61K31/5377A61K31/517A61P25/18A61P25/16
Inventor 付伟镇学初沈庆熊子君邓欣贤
Owner FUDAN UNIV