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Dopamine D2 receptor selective agonist and application thereof

A technology for selecting, isomers, applied in the field of structural pharmacology research in life sciences, can solve problems such as inability to distinguish receptor subtypes

Active Publication Date: 2020-12-08
CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the similarity of the different subtypes within the two families of dopamine receptors, although it is easy for dopamine ligand compounds to distinguish the D1 and D2 families, most compounds cannot distinguish the receptor subtypes of the same family

Method used

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  • Dopamine D2 receptor selective agonist and application thereof
  • Dopamine D2 receptor selective agonist and application thereof
  • Dopamine D2 receptor selective agonist and application thereof

Examples

Experimental program
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preparation example Construction

[0163] The present invention also provides a method for preparing a pharmaceutical composition or preparation for treating low dopamine-related diseases, the method comprising: mixing a therapeutically effective amount of a compound of formula I with a pharmaceutically acceptable carrier to form a pharmaceutical composition or preparation.

[0164] Typically, administering a therapeutically effective amount of a compound of formula I, or a pharmaceutical composition or preparation comprising a compound of formula I, to a subject can treat or alleviate low dopamine-related diseases (eg, Parkinson's).

[0165] DRD2 selective agonists and uses thereof

[0166] The invention provides a DRD2 selective agonist.

[0167] Typically, the present invention discovers and identifies a DRD2 selective agonist.

[0168] In a preferred example of the present invention, the inventors synthesized a DRD2 selective agonist by chemical method based on the continuous optimization design of the DR...

Embodiment 1

[0188] Example 1 Discovery and Identification of a Dopamine D2 Receptor Selective Agonist

[0189] Inventor based on D 2 Based on the receptor structure information, a DRD2 selective agonist I-2 ( figure 1 ). The inventors selected two signaling pathways downstream of the receptor, the G protein signaling pathway and the β-arrestin signaling pathway, as indicators of the degree of receptor agonism, and verified their selectivity at the cellular level.

[0190] result( figure 2 ) showed that this agonist behaved similarly in the two signaling pathways, both for the activation of the dopamine receptor downstream G protein signaling pathway ( figure 2 a) Or for activating the downstream β-arrestin signaling pathway of dopamine receptors ( figure 2 b), this agonist cannot activate DRD3 and DRD4 but activates both DRD2, so it can be seen that this agonist is highly selective for DRD2. In order to further explore its specificity, the inventor screened its agonism to other 32...

Embodiment 2

[0191] Embodiment 2 dopamine D 2 Potential Application Value of Receptor Selective Agonists in Disease Treatment

[0192] The inventor optimized the design and screened out a DRD2 highly selective agonist. Based on its selectivity, it can minimize the side effects caused by DRD3 and DRD4, so it has better application value in disease treatment and is used for It is possible to treat Parkinson's disease, attention deficit hyperactivity disorder, pituitary tumor, hyperprolactinemia, restless legs syndrome, negative schizophrenia and other low dopamine-related diseases.

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PUM

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Abstract

The invention relates to a dopamine D2 receptor selective agonist and application thereof. Specifically, the invention discloses an agonist with selectivity to DRD2 and discloses a potential application value of the agonist in disease treatment. The invention discloses an agonist with DRD2 selectivity for the first time, and the specific targeting DRD2 of the agonist can play a role in treating low dopamine related diseases such as Parkinson's disease, attention deficit hyperactivity disorder, pituitary adenoma, hyperprolactinemia, hyperactivity leg syndrome, negative schizophrenia and the like while side effects are reduced to the maximum extent.

Description

technical field [0001] The discovery belongs to the field of structural pharmacology research in life sciences, specifically a dopamine D 2 Discovery of receptor selective agonists and their application in disease treatment. Background technique [0002] Dopamine receptors belong to the family of G protein-coupled receptors. Currently, five types of dopamine receptors have been isolated. According to their biochemical and pharmacological properties, they can be divided into D 1 Class and D 2 class, where D 1 class receptors including D 1 and D 5 Isotype, which can activate adenylate cyclase and increase intracellular cyclic adenylate (cAMP) concentration; D 2 class receptors including D 2 、D 3 and D 4 The isoform has inhibitory effects on adenylate cyclase and is also associated with other intracellular second messenger systems, including activation of potassium channels, inhibition of calcium channels, and conversion of phosphatidylinositol. The carboxy-terminus (C...

Claims

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Application Information

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IPC IPC(8): C07C217/62C07C213/02A61K31/137A61P25/16A61P25/14A61P35/00A61P15/14A61P25/18
CPCC07C217/62A61P25/16A61P25/14A61P35/00A61P15/14A61P25/18C07C2601/08C07C2601/14C07C2601/18C07C2601/02
Inventor 汪胜程建军樊鲁玉谭亮聂芬
Owner CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI
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