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GPR35 receptor novel agonist and application thereof

An agonist and receptor technology, applied in the field of targeting active molecules and their applications, can solve the problems of single structure and low activity

Inactive Publication Date: 2020-04-10
TAIZHOU GUOKEHUAWU BIOMEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In view of the problems of low activity and single structure of GPR35 receptor agonists in the study of elucidating the biology and pharmacology of GPR35 receptors, finding new and potential ligands is very important for elucidating the biology and pharmacology of GPR35 receptors. Pharmacological functions and the development of drugs targeting the GPR35 receptor are highly desirable
[0004] At present, about rhein of the present invention, quercetin, 7-desmethyl ginkgobiflavone, protohypericin, baicalin, tetrahydrodimethoxydibenzoquinoline diol, aloe-emodin, Meboldine, daidzein, tanshinone IIA, osmanthus licorice, magnolialine, cryptotanshinone, and isoxanthanol have been proven to have an agonistic effect on the GPR35 receptor by technical means. The technical scheme has not been reported yet

Method used

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  • GPR35 receptor novel agonist and application thereof
  • GPR35 receptor novel agonist and application thereof
  • GPR35 receptor novel agonist and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: Construction of GPR35 receptor screening model

[0031] Materials Minbutanol and ML145 were purchased from Sigma; natural compounds were purchased from Shanghai Yuanye Biotechnology Co., Ltd., and CHO-hGPR35 cells were obtained by transfection and screening by our company. The detection platform is the third generation of Corning Imager, the detected signal is the wavelength shift caused by cell dynamic mass reset (DMR).

[0032] The agonistic probe of GPR35 receptor is gentianol, and the antagonistic probe is ML145. Firstly, based on the unlabeled cell integrated pharmacology technology, the present invention uses the probes Protonne and ML145 on CHO-hGPR35 cells to establish models for agonism analysis, desensitization analysis and antagonism analysis, laying the foundation for subsequent screening of natural compounds. The CHO-hGPR35 cells in the logarithmic growth phase were inoculated in different wells of a 384-well cell plate, the inoculation volume...

Embodiment 2

[0033] Example 2: Preliminary screening of natural compounds on the GPR35 receptor model

[0034] The CHO-hGPR35 cells in the logarithmic growth phase were inoculated in different wells of a 384-well cell plate, the inoculation volume of each well was 40 μL, and the number of cells inoculated in each well was 1×10 4 First, the inoculated cell plate was placed in a cell culture incubator for 24 h and then the experiment was carried out. Firstly, monitor the response signal of the compound to be screened (final concentration is 100 μM) acting on CHO-hGPR35 cells; Influence of the response signal on the cell.

[0035] All compounds acted on CHO-hGPR35 cells at a final concentration of 100 μM, and the resulting DMR response signal intensity is shown in figure 2 A; After compound pretreatment of CHO-hGPR35 cells for 1h, the DMR response signal intensity of adding 200nM fentanil is shown in figure 2 b. According to the basis for the judgment of new GPR35 receptor agonists - th...

Embodiment 3

[0036] Example 3: Validation of target specificity of active compounds

[0037] by comparison figure 2 A and 2B, it is inferred that the above compounds have an agonistic effect on the GPR35 receptor, but the target specificity of these compounds needs further verification. Compounds with agonistic activity need to use GPR35-specific antagonist ML145 to verify whether the generated DMR signal can be inhibited, so as to determine whether it is GPR35-specific agonism.

[0038] The CHO-hGPR35 cells in the logarithmic growth phase were inoculated in different wells of a 384-well cell plate, the inoculation volume of each well was 40 μL, and the number of cells inoculated in each well was 1×10 4 First, the inoculated cell plate was placed in a cell culture incubator for 24 h and then the experiment was carried out. First, the agonistic and desensitizing effects of the above 38 compounds were repeatedly verified, and then CHO-hGPR35 cells were treated with ML145 (final concentrat...

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Abstract

The invention relates to a targeting active molecule in a natural product and an application thereof, and in particular relates to a GPR35 receptor new agonist in the natural product and an application thereof. The GPR35 receptor new agonist comprises the active ingredients of one or more than two of compounds of rheinic acid, quercetin, 7-demethylated gingko biflavone, prohypericin, baicalin, tetrahydrodimethoxydibenzoquinoline diol, aloe-emodin, norbodine, daidzein, tanshinone IIA, sweet clover, magnoflorine, cryptotanshinone and isofulvic alcohol and corresponding pharmaceutically acceptable salt forming compounds. In-vitro cell experiments show that natural compounds included in the GPR35 receptor new agonist have an agonistic effect on the GPR35 receptor. At present, researches show that the GPR35 receptor is closely related to asthma, heart failure, hypertension, inflammation, coronary heart disease, metabolic syndrome, pain, cancer and other diseases. The GPR35 receptor novel agonist provides candidate compounds for drug development of the related diseases.

Description

technical field [0001] The invention relates to targeting active molecules in natural products and applications thereof, in particular to new agonists of GPR35 receptors in natural products and applications thereof. Background technique [0002] GPR35 receptor is an orphan receptor in the G protein-coupled receptor family, and its biological function is not very clear. GPR35 receptors are expressed in immune cells such as leukocytes, monocytes, neutrophils, T cells, and dendritic cells, and in various tissues such as pancreas, small intestine, colon, and spleen. With the screening of small molecule compound libraries and the discovery of potential endogenous agonists, it has been gradually proved that GPR35 receptors may be related to diseases such as pain, hypertension, coronary artery disease, early-onset inflammatory diseases, inflammation and asthma, so GPR35 receptor is very likely to be a novel and potential therapeutic target. [0003] Natural products have always b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/122A61K31/7048A61K31/352A61K31/58A61K31/473A61K31/19A61K31/05A61P11/06A61P9/12A61P29/00A61P3/00A61P35/00A61P9/04A61P9/10
CPCA61K31/122A61K31/7048A61K31/352A61K31/58A61K31/473A61K31/19A61K31/05A61P11/06A61P9/12A61P29/00A61P3/00A61P35/00A61P9/04A61P9/10
Inventor 梁鑫淼单彩龙王纪霞王志伟刘艳芳于广璞薛珍珍
Owner TAIZHOU GUOKEHUAWU BIOMEDICAL TECH CO LTD
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