CN107661328A - Application of the furocoumarin compound in Claritin is prepared - Google Patents
Application of the furocoumarin compound in Claritin is prepared Download PDFInfo
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- CN107661328A CN107661328A CN201711132444.0A CN201711132444A CN107661328A CN 107661328 A CN107661328 A CN 107661328A CN 201711132444 A CN201711132444 A CN 201711132444A CN 107661328 A CN107661328 A CN 107661328A
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- claritin
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- mrgprx2
- furocoumarin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
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Abstract
The invention provides a kind of application of furocoumarin compound in Claritin is prepared, belong to biomedicine technical field.The present invention confirms that furocoumarin compound effectively can cause people's mast cell KU812 β hexosaminidases to discharge by antagonism by C48/80 first, and then can suppress anaphylactoid reaction, and proves that its action receptor is MrgprX2 acceptors first；Furocoumarin compound is prepared into antiallergy preparation, by abundant Claritin type, brand-new selection and strategy are provided for antianaphylactic treatment.
Description
Technical field
The invention belongs to biomedicine technical field, more particularly to furocoumarin compound is preparing Claritin
In application.
Background technology
Medicine anaphylactoid reaction, which is derived from medicine, directly stimulates mast cell or basophilic granulocyte, causes mast cell to take off
Particle release Hex, histamine isoreactivity mediator and trigger.Clinically, it is possible to send out during patient's medication first
Raw anaphylactoid reaction, as a result not only brings huge financial burden to patient, will also result in new pain even life threat.Grind
Anaphylactoid reaction can be mediated by studying carefully finder source MrgprX2 acceptors (Mas correlation G-protein Ou Lian acceptor X2), when medicine irritation people source
After MrgprX2 acceptors, mast cell calcium ion concentration can be caused to raise and trigger degranulation to react, and then cause anaphylactoid reaction
Occur.Clinically Claritin used mainly includes Loratadine, allergic reaction medium sustained-release agent and amcinonide
Thing.Antagonism MrgprX2 acceptors can cause anaphylactoid reaction to be stuck in source, but the Claritin of antagonism MrgprX2 acceptors
Or blank out, therefore the research of MrgprX2 receptor antagonists has been to be concerned by more and more people, drug antagonism MrgprX2
The purpose of acceptor is mainly so that the generation that anaphylactoid reaction is prevented from source, fundamentally solves the harm of anaphylactoid reaction,
It is significant to the exploitation of antiallergy drug candidate to develop MrgprX2 receptor antagonists or lead compound.
The content of the invention
It is rich it is an object of the invention to provide a kind of application of furocoumarin compound in Claritin is prepared
Rich Claritin type, brand-new selection and strategy are provided for antianaphylactic treatment.
The present invention is to be achieved through the following technical solutions：
A kind of application of furocoumarin compound in Claritin is prepared.
Preferably, the furocoumarin compound is Imperatorin, Isomperatorin or phellopterin.
Preferably, the Claritin is the medicine for antagonism MrgprX2 acceptors.
Preferably, the Claritin is to be discharged for suppressing people's mast cell KU812 Hex
Medicine.
Preferably, the Claritin is clinically-acceptable pharmaceutical preparation.
Preferably, described pharmaceutical preparation is tablet, capsule, granule or injection.
Compared with prior art, the present invention has technique effect beneficial below：
The present invention confirms that furocoumarin compound effectively can be drawn antagonism by compound 48/80 (C48/80) first
People's mast cell KU812 Hex release is played, and then anaphylactoid reaction can be suppressed；By furocoumarin class
Compound is prepared into antiallergy preparation, and by abundant Claritin type, brand-new selection and strategy are provided for antianaphylactic treatment.
Brief description of the drawings
Fig. 1 is that the Imperatorin of various concentrations suppresses the Hex release knot of the KU812 as caused by C48/80
Fruit is schemed, wherein, C48/80 is used as blank control (Control) as positive control agent using TM buffer solutions.
Fig. 2 is that the Isomperatorin of various concentrations suppresses the Hex release of the KU812 as caused by C48/80
Result figure, wherein, C48/80 is used as blank control (Control) as positive control agent using TM buffer solutions.
Fig. 3 is that the phellopterin of various concentrations suppresses the Hex release knot of the KU812 as caused by C48/80
Fruit is schemed, wherein, C48/80 is used as blank control (Control) as positive control agent using TM buffer solutions.
Fig. 4 is retention behavior of the Imperatorin on MrgprX2-HEK293 membrane flexibility posts.
Fig. 5 is retention behavior of the Isomperatorin on MrgprX2-HEK293 membrane flexibility posts.
Fig. 6 is retention behavior of the phellopterin on MrgprX2-HEK293 membrane flexibility posts.
Embodiment
With reference to specific embodiment, the present invention is described in further detail, it is described be explanation of the invention and
It is not to limit.
Imperatorin (structural formula such as Formulas I), Isomperatorin (structural formula such as Formula II) and phellopterin (structural formula such as formula
III it is) to screen to find by MrgprX2 acceptors high expressing cell membrane chromatography early stage (CMC), these three furocoumarin class chemical combination
Thing has good affinity with MrgprX2 acceptors.Therefore, body is used according to its affinity interaction with MrgprX2 acceptors, applicant
The experiment of outer cellular pharmacology, using the KU812 cell models of the high expression MrgprX2 acceptors of cell surface, investigated they to by
The inhibitory action of the Hex release of KU812 caused by C48/80.Result of study shows：Three kinds of furocoumarin classes
Compound (Imperatorin, Isomperatorin and phellopterin) can effectively suppress β-ammonia of the KU812 as caused by C48/80
The release of base hexoside enzyme, it is potentially to prepare antianaphylactic medicine to illustrate these three furocoumarin compounds.
Technical scheme is further illustrated below by way of specific embodiment.
Embodiment 1
1. experiment material
Instrument：Full-automatic microplate reads instrument and is purchased from Bio-Rad companies (California, the U.S.).
Cell line：KU812 is cultivated in the IMEM culture mediums of 10% serum, adds 1: 100 Pen .- Strep.Culture medium
Cell is set to maintain 2 × 10 per being replaced every other day with fresh culture half6The density of individual cells/ml.
Main agents：TM cushioning liquid (composition (g/L)：6.954 NaCl, 0.353 KCl, 2.383 HEPES,
0.162 KH2PO4, 0.282 CaCl2, 0.143 MgSO4, 0.991 glucose, 1 bovine serum albumin(BSA).Dimethyl is sub-
Sulfone is purchased from Jinhuada Chemical Agent Co., Ltd., Guangzhou City, and C48/80 is purchased from Sigma-Aldrich (St.Louis, MO, USA).
Imperatorin, Isomperatorin and phellopterin are purchased from Chengdu Puffy moral bio tech ltd (Chengdu, China).
Triton X-100 are purchased from Ke Hao bio-engineering corporations (Xi'an, China), D-glucose Tianjin Ke Miou chemical reagents corporations
(Tianjin, China), bovine serum albumin(BSA) and HEPES are purchased from MP biomedicines Co., Ltd (France).
2. experimental method
(1) Hex discharges
KU812 cells are inoculated in 96 orifice plates, 30000 cells/wells, overnight incubation.96 orifice plates by 1500rpm from
After heart 5min, former culture medium is abandoned in suction, according to default packet, is separately added into different medicines：Blank control group adds 90 μ L TM
Buffer solution, administration group add 30 μ g/mL C48/80 solution of 90 μ L medicines to be tested, and negative control group adds the μ g/ of 90 μ L 30
ML C48/80 solution.5min is centrifuged in incubator 37 DEG C of incubations 30min, rear 1500rpm, 50 μ L are drawn to new bore in each hole respectively.
The remaining TM buffer solutions of negative control group are inhaled again after abandoning, add 90 μ L 0.1%Triton X-100 lysates, blow and beat, stand
5min, then 1500rpm centrifuge 5min after take 50 μ L to new bore be cracking group.50 μ L beta-amino hexoses are added to each hole.37℃
The Na in 150 μ L/ holes is added after incubation 90min2CO3/NaHCO3Terminate liquid, it is positioned on shaking table and is mixed with 50 turns/min frequency
2min.Its absorbance is determined in 405nm.
Hex release rate is calculated as follows.
Hex release rate=(test group OD values/(blank control group OD values+cracking group OD)) × 100%；
Wherein, the test group OD values are blank control group OD values, administration group OD values or negative control group OD values.
3. experimental result
Data mean ± standard error (mean ± SEM) expression, graph making application Graphpad Prism5.0 softwares.
Through statistics, each group compound suppresses the result such as table 1-3. of the Hex release of KU812 cells
The Hex releasing result that Imperatorin suppresses the KU812 cells as caused by C48/80 is illustrated in table 1
In Fig. 1, wherein, Control is blank control group, and C48/80 is negative control group, and various concentrations represent the Europe in administration group
The concentration of peucedanin.
The Imperatorin of table 1 suppresses the Hex release rate (%) of the KU812 cells as caused by C48/80
Fig. 1 be Imperatorin suppress the KU812 cells as caused by C48/80 Hex release figure (relative to
Negative control group, * P<0.05, * * P<0.01, * * * P<0.001, n=4).
The Imperatorin for finding 10 μM, 50 μM, 100 μM and 200 μM by table 1 and Fig. 1 is counting in contrast to negative control group
On, there is significant difference (P<0.05).Illustrate that Imperatorin can dose-dependently suppress as caused by C48/80
The Hex release of KU812 cells.
The Hex releasing result that Isomperatorin suppresses the KU812 cells as caused by C48/80 is illustrated in table
In 2 and Fig. 2, wherein, Control is blank control group, and C48/80 is negative control group, and various concentrations represent different in administration group
The concentration of Imperatorin.
The Isomperatorin of table 2 suppresses the Hex release rate (%) of the KU812 cells as caused by C48/80
Fig. 2 is that Isomperatorin suppresses the Hex release figure of the KU812 cells as caused by C48/80 (relatively
In negative control group, * P<0.05, * * P<0.01, * * * P<0.001, n=4).
The Isomperatorin for finding 10 μM, 50 μM, 100 μM and 200 μM by table 2 and Fig. 2 is being united in contrast to negative control group
On meter is learned, there is significant difference (P<0.001).Illustrate that Isomperatorin can dose-dependently suppress to be caused by C48/80
KU812 cells Hex release.
The Hex releasing result that phellopterin suppresses the KU812 cells as caused by C48/80 is illustrated in table 3
In Fig. 3, wherein, Control is blank control group, and C48/80 is negative control group, and various concentrations represent the coral in administration group
The concentration of coral dish element.
The phellopterin of table 3 suppresses the Hex release rate (%) of the KU812 cells as caused by C48/80
Fig. 3 be phellopterin suppress the KU812 cells as caused by C48/80 Hex release figure (relative to
Negative control group, * P<0.05, * * P<0.01, * * * P<0.001, n=4)
The phellopterin for finding 50 μM by table 3 and Fig. 3 statistically, has conspicuousness poor in contrast to negative control group
Different (P<0.05).Illustrate that phellopterin can dose-dependently suppress to suppress β-ammonia of the KU812 cells as caused by C48/80
Base hexoside enzyme r e lease.
Embodiment 2
1. experiment material
Instrument：LC-2010AHT (SHIMAZU), make packing column machine by oneself.
Cell line：MrgprX2-HEK293 cell culture culture medium be 10% hyclone DMEM culture mediums in,
Add the 5%CO of 1: 100 Pen .- Strep2, in 37 DEG C of environment.Culture medium is good for cell with fresh culture medium every other day
Kang Shengcun.
Main agents：DMEM culture mediums are purchased from Hyclone (Utah State Luo Gen cities, the U.S.), macropore silicon with hyclone
Glue is purchased from Qingdao Makall Group Co., Ltd. (Qingdao, China).
2. experimental method
The preparation of 2.1MrgprX2-HEK293 cell membrane stationary phases
Take above-mentioned MrgprX2-HEK293 cells (about 7 × 106Individual cell) suspension, used under the conditions of 1000rpm, 4 DEG C
5min is centrifuged, supernatant is abandoned, takes bottom cell；The cell centrifuged is washed 2 times with 5mL physiology salts, then the cell that will have been obtained
Tris-Hcl 5mL ultrasonic 30min under condition of ice bath are added to crush, then it is broken with cell crushing instrument (400W, 8 times, each 3S)
Afterwards, 5000rpm pelleted by centrifugation 10min, takes supernatant；20min is centrifuged under 12000g, abandons supernatant, is blown with 10mL physiological saline
Cell membrane suspension is obtained after dissipating.Weigh respective amount macro porous silica gel 45mg (purified, 5 μm,) it is put in 105 DEG C of baking ovens
Activate 30min.It will be placed in ice in the above-mentioned tool test tube equipped with the silica gel activated, with 10mL syringes, be vortexed
After lower cell membrane suspension of state is sufficiently mixed 5min with silica gel, after magnetic stirrer 30min (in 4 DEG C of refrigerators), 4
Stood overnight in DEG C refrigerator；Next day, 5min is centrifuged under the conditions of 800g centrifugal force with 5mL physiological saline, 3 times.Do not connect with washing away
Close the cell membrane on silica gel.
The preparation of 2.2MrgprX2-HEK293 membrane flexibility posts
Enter luggage post with self-control packing column machine, fill column flow rate 2.0mL/min, fill post time 10min, chromatographic column puts 4 DEG C of refrigerators
In it is stand-by.
The chromatographic condition of 2.3MrgprX2-HEK293 cell membranes
The chromatographic condition of MrgprX2-HEK293 cell membranes is that mobile phase is water, flow 0.2mL/min, 37 DEG C of column temperature,
Detector wavelength is 254nm.
The reservation of 2.4 Imperatorins, Isomperatorin and phellopterin on MrgprX2-HEK293 membrane flexibility posts
Behavior
1.0mg/mL Imperatorin is recorded respectively, and 1.0mg/mL Isomperatorins and 1.0mg/mL phellopterins exist
Retention behavior on MrgprX2-HEK293 membrane flexibility posts.
3. experimental result
1.0mg/mL Imperatorin, 1.0mg/mL Isomperatorins and 1.0mg/mL phellopterins are in MrgprX2-
Retention behavior on HEK293 membrane flexibility posts is respectively such as Fig. 4, Fig. 5 and Fig. 6.Imperatorin, Isomperatorin and glehnia littoralis
Element has good reservation on MrgprX2-HEK293 membrane flexibility posts, it was demonstrated that Imperatorin, Isomperatorin and coral
Dish element is acted on MrgprX2 acceptors.
4. conclusion
By above-mentioned test result indicates that, furocoumarin compound (Imperatorin, Isomperatorin and glehnia littoralis
Element) can effectively antagonism KU812 as caused by C48/80 Hex discharge, wherein before with Imperatorin and different Europe
Hu Suwei is optimal.
In summary experiment can show that present invention finds furocoumarin compound (Imperatorin, different Imperatoria ostruthium
Element and phellopterin) new pharmacological action, i.e. its beta-amino hexoside with good antagonism KU812 as caused by C48/80
Enzyme r e lease acts on, and has opened up the new clinical practice field of traditional Chinese medicinal components, significant to exploitation Claritin.
The invention discloses a kind of application of furocoumarin compound in Claritin is prepared, and the present invention is first
It was found that furocoumarin compound has the function that the anaphylactoid reaction as caused by C48/80 of antagonism mast cell, and act on
Acceptor is MrgprX2 acceptors.In vitro cell experiment is carried out to furocoumarin compound, have selected and show high expression
People's mast cell line KU812 of MrgprX2 acceptors.Them have been investigated to causing people's mast cell KU812 β-ammonia by C48/80
The antagonism of base hexoside enzyme r e lease.Result of study show furocoumarin compound can effectively antagonism by C48/80
People's mast cell KU812 Hex is caused to discharge, it is potentially to be used to make to illustrate furocoumarin compound
Standby antianaphylactic medicine, the present invention provide a kind of brand-new selection and thinking for the treatment of current anaphylactoid reaction, widened
The selection field of Claritin, the also development for the technical field are made that contribution；The present invention is that have clear and definite chemical constitution
Compound, can quantify to feed intake during for pharmacy, for preparing modern formulation, there are the potentiality for developing into Claritin.
The present invention is the compound for having clear and definite chemical constitution, can quantify to feed intake during for pharmacy, is advantageously used for preparing existing
For formulation.
Claims (6)
1. application of the furocoumarin compound in Claritin is prepared.
2. application as claimed in claim 1, it is characterised in that the furocoumarin compound is Imperatorin, different Europe
Peucedanin or phellopterin.
3. application as claimed in claim 1, it is characterised in that the Claritin is for antagonism MrgprX2 acceptors
Medicine.
4. application as claimed in claim 1, it is characterised in that the Claritin is for suppressing people's mast cell
The medicine of KU812 Hex release.
5. application as claimed in claim 1, it is characterised in that the Claritin is clinically-acceptable pharmaceutical preparation.
6. application as claimed in claim 1, it is characterised in that described pharmaceutical preparation is tablet, capsule, granule or note
Penetrate agent.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711132444.0A CN107661328B (en) | 2017-11-15 | 2017-11-15 | Furocoumarin compound is preparing the application in Claritin |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711132444.0A CN107661328B (en) | 2017-11-15 | 2017-11-15 | Furocoumarin compound is preparing the application in Claritin |
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| CN107661328A true CN107661328A (en) | 2018-02-06 |
| CN107661328B CN107661328B (en) | 2019-08-23 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108398517A (en) * | 2018-02-11 | 2018-08-14 | 湖南正清制药集团股份有限公司 | A kind of method of potential Allergen in screening Zhengqingfengtongning preparation |
| CN108619183A (en) * | 2018-06-04 | 2018-10-09 | 西安交通大学 | The simple extraction methods of coumarin kind compound and its application in a kind of root of Dahurain angelica |
| CN110151768A (en) * | 2019-05-08 | 2019-08-23 | 西安交通大学 | A kind of pharmaceutical composition and its application with antiasthmatic activity |
| CN110251507A (en) * | 2019-07-04 | 2019-09-20 | 西安交通大学 | A kind of medicinal application of the asthma caused for Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 |
| WO2020229648A1 (en) * | 2019-05-16 | 2020-11-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method to treat type 2 inflammation or mast-cell dependent disease |
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2017
- 2017-11-15 CN CN201711132444.0A patent/CN107661328B/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108398517A (en) * | 2018-02-11 | 2018-08-14 | 湖南正清制药集团股份有限公司 | A kind of method of potential Allergen in screening Zhengqingfengtongning preparation |
| CN108619183A (en) * | 2018-06-04 | 2018-10-09 | 西安交通大学 | The simple extraction methods of coumarin kind compound and its application in a kind of root of Dahurain angelica |
| CN110151768A (en) * | 2019-05-08 | 2019-08-23 | 西安交通大学 | A kind of pharmaceutical composition and its application with antiasthmatic activity |
| WO2020229648A1 (en) * | 2019-05-16 | 2020-11-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method to treat type 2 inflammation or mast-cell dependent disease |
| CN110251507A (en) * | 2019-07-04 | 2019-09-20 | 西安交通大学 | A kind of medicinal application of the asthma caused for Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 |
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| CN107661328B (en) | 2019-08-23 |
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