Selective agonist of dopamine D2 receptor (DRD2) and application thereof in treatment of diseases

A technology of precursors and isomers, applied in the field of discovery of dopamine D2 receptor selective agonists, can solve problems such as hallucinations and movement disorders

Active Publication Date: 2020-10-23
CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since D 2 The receptors are highly similar, so there is no selective DRD2 agonist clinically, and most drugs will act on DRD2 as well as D 3 and D 4 Both subtypes work to produce corresponding side effects such as dyskinesias or hallucinations

Method used

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  • Selective agonist of dopamine D2 receptor (DRD2) and application thereof in treatment of diseases
  • Selective agonist of dopamine D2 receptor (DRD2) and application thereof in treatment of diseases
  • Selective agonist of dopamine D2 receptor (DRD2) and application thereof in treatment of diseases

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preparation example Construction

[0154] 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.

[0155] 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).

[0156] DRD2 selective agonists and uses thereof

[0157] The invention provides a DRD2 selective agonist.

[0158] In a preferred example of the present invention, based on the complex structure of DRD2 and the antagonist haloperidol, the inventors continuously optimized the design and synthesized a DRD2 selective agonist by chemical method.

[0159] In another preferred exampl...

Embodiment 1

[0181] Embodiment 1 A kind of dopamine D 2 Discovery and Characterization of Receptor Selective Agonists

[0182] Inventor based on D 2 Based on the structural information of the receptor, a DRD2 selective agonist ( 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.

[0183] result( figure 2 ) shows that the performance of this agonist in the two signaling pathways is similar, whether it is for the activation of the G protein signaling pathway downstream of the dopamine receptor or for the activation of the β-arrestin signaling pathway under the dopamine receptor, the agonist has the same effect. Cannot activate DRD4, partially activate DRD3, fully activate DRD2, and the EC when this agonist plays a role in DRD3 50The value is about 15 times that of DRD2, which shows...

Embodiment 2

[0184] Embodiment 2 dopamine D 2 Application of receptor selective agonists in the treatment of animal models of Parkinson's disease

[0185] The inventors tested the neuroprotective effect of DRD2 agonist in the MPTP-induced Parkinson's disease mouse model, meanwhile, the Parkinson's disease drug pramipexole served as a positive control. result( image 3 ) showed that this agonist can relieve the MPTP-induced decrease in the expression of dopamine synthase tyrosine hydroxylase (TH) in the substantia nigra of the brain, revealing that it has a protective effect on dopaminergic neurons in the substantia nigra, And its effect is better than pramipexole (DRD2 / DRD3 / DRD4 agonist), which is currently clinically used to treat Parkinson's disease, which further suggests that this DRD2 agonist has the potential to treat Parkinson's disease more effectively.

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Abstract

The invention relates to a selective agonist of DRD2 and application thereof in treatment of diseases. Specifically, the invention discloses an agonist with high selectivity to DRD2 for the first time. The structure of the agonist is shown as a formula I. The selective agonist can be used as a medicine for treating diseases related low dopamine, e.g., the Parkinson's disease. Further animal experiments show that the selective agonist can be used for treating the Parkinson's disease, so a new hope is brought to treatment of patients with the Parkinson's disease; with the Parkinson's disease asan example, it is proved that the selective agonist can be used as a medicine for treating other low-dopamine related diseases such as attention deficit hyperactivity disorder, pituitary adenoma, hyperprolactinemia, hyperactivity leg syndrome and negative schizophrenia.

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. A number of studies hav...

Claims

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Application Information

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IPC IPC(8): C07D307/81C07D407/12A61P25/16A61P25/14A61P35/00A61P7/00A61P25/18A61K31/343A61K31/351
CPCC07D307/81C07D407/12A61P25/16A61P25/14A61P35/00A61P7/00A61P25/18
Inventor 汪胜程建军樊鲁玉谭亮陈章成
Owner CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI
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