Medicinal use of 4-(4-phenylpiperazino)quinazoline derivatives

A technology of quinazolines and phenylpiperazines, applied in the field of biopharmaceuticals, can solve the problems of complex pathogenesis and unclear pathogenesis of schizophrenia

Inactive Publication Date: 2012-11-21
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, envi...

Method used

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  • Medicinal use of 4-(4-phenylpiperazino)quinazoline derivatives
  • Medicinal use of 4-(4-phenylpiperazino)quinazoline derivatives
  • Medicinal use of 4-(4-phenylpiperazino)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 Receptors (Ellen Y. T. Chien, Wei Liu, Qiang Zhao, Vsevolod Katritch, Gye Won Han, Michael A. Hanson, Lei Shi, Amy Hauck Newman, Jonathan A. Javitch, Vadim Cherezov, Raymond C. Stevens. Science 330, (2010 ) 1091-1095. The PDB number is 3PBL) for energy optimization to exclude unreasonable structures in the receptor, thus obtaining the following figure 1 Optimized D shown 3 The three-dimensional structure of the receptor.

Embodiment 2

[0026] Example 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 detection 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] The Catalyst module of Discovery Studio was used to c...

Embodiment 3

[0029] Example 3 Virtual screening and bioactivity testing based on receptor pharmacophore model

[0030]Use the best flexible method of the Catalyst module of the Discovery Studio program to search the MayBridge database (containing 61602 compounds), according to the matching value (Fit Value) of the small molecule and the pharmacophore, the docking of the small molecule and the receptor, the G-Score scoring function, and Small molecule ADMET property prediction results, 7 candidate compounds were selected from the ASINEX small molecule database (http: / / www.asinex.com), purchased from the Netherlands ASINEX company 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 that the fina...

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PUM

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Abstract

The invention belongs to the field of biological pharmacy, relates to a medicinal use of 4-(4-phenylpiperazino)quinazoline derivatives and especially relates to a use of the 4-(4-phenylpiperazino)quinazoline derivatives in preparation of drugs for treating nervous system diseases and especially in preparation of dopamine D3 receptor inhibitors. A result of a biological activity test shows that the 4-(4-phenylpiperazino)quinazoline derivatives have good effects of inhibiting D3 receptors. The 4-(4-phenylpiperazino)quinazoline derivatives can be used as drug lead compounds, be synthesized into dopamine D3 receptor inhibitors, and be further used for preparation of drugs for treating schizophrenia and Parkinsonism 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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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
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