CN107129439A - A kind of compound, muscarine m receptor antagonist, composition and application - Google Patents
A kind of compound, muscarine m receptor antagonist, composition and application Download PDFInfo
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- CN107129439A CN107129439A CN201610107392.0A CN201610107392A CN107129439A CN 107129439 A CN107129439 A CN 107129439A CN 201610107392 A CN201610107392 A CN 201610107392A CN 107129439 A CN107129439 A CN 107129439A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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Abstract
The invention discloses the discovery and application of the hydroxy cinnamate amides compound action target spot separated in a kind of plant of Solanaceae, specifically hydroxy cinnamate amides compound N1, the application in the discovery and spasmolysis medicine of N8 Bis (dihydrocaffeoyl) spermidine (abbreviation BDCS) action target spot.The present invention is by using n cell target spot pharmacological techniques, it was found that this compound has stronger muscarine m receptor antagonistic activity, quantitative dose-effect relationship shows dose-dependently DMR response signals caused by antagonism acetylcholine, and it is muscarine m receptor antagonist to show BDCS.The muscarine m receptor antagonist is with one or both of BDCS and BDCS pharmaceutically acceptable salts above for active component.Current study show that the disease such as muscarine m receptor and spasm, analgesia, calmness, schizophrenia is related, it can provide action target spot clearly efficiently new part for relevant disease accordingly.
Description
Technical field
The invention belongs to the discovery of biological active constituents from natural medicines mechanism of action and application field, and in particular to a kind of spasmolysis is lived
Spasmolysis mechanism of property composition and application thereof.
Background technology
Anisodus tanguticus Anisodus tanguticus are the plant that Solanaceae Tangut Anisodus Radix belongs to, and are the endemic plants of China,
Tibetan language claims " Tang Chuanna guarantors ".The ground such as Gansu, Tibet, Yunnan, the Qinghai of China's Mainland are distributed in, 2,800 meters of height above sea level are grown on extremely
4,200 meters of area, is typically grown in hillside and grass slope Yang Chu, at present not yet by artificial introducing and planting.As traditional Tibetan medicine,
Tibetan medicine is used as medicine with Anisodus tanguticus and seed, the effect [1] with analgesia.Chemical composition on Anisodus tanguticus
Research is rarely reported, and is Tropane alkaloids such as hyoscyamine, hyoscine, anisodamine and anisodine [2] mostly.Tropine alkanes
Alkaloid is also that the medicinal ingredient being widely known by the people all the time in Anisodus tanguticus is that nineteen sixty offers birthday congratulations river etc. with the medicinal material
Tropane alkaloids improve microcirculation disorder, have saved the life of a large amount of meningitis children；Anisodamine makes fulminant type epidemic meningitis
Case fatality rate be down to 10% or so [3] by past more than 50%.Recently chemical composition removes tropine in report Anisodus tanguticus
Outside alkanes alkaloid, an also class hydroxy cinnamate amide alkaloid, author reports the compound town of this class formation in document
Pain activity, its action target spot is opiate receptor [4].And the relation between this kind of compound and M M-ChRs was not reported.
Spasm is clinically common disease, refers to that muscle does nonvoluntary contracture suddenly, is commonly called as knotting, and can make the prominent sense of patient
Severe pain, muscle movement is uncoordinated, the spasm such as common shank, thigh, hand, foot, bladder.Angina medically dactylospasm it is violent
Pain and with the sensation of vexed plug, the espespecially vexed plug property pain (angina pectoris) of chest, clinical common internal organ angina (eilema), the heart are twisted
Bitterly, renal colic, cholecystalgia etc..Mostly spasm and angina caused [5] by the abnormal contraction of muscle.
Muscarine m receptor is relevant with the contraction and diastole of body of gland and smooth muscle, and the antagonist of m receptor has diastole smooth muscle
Effect, can be clinically used for spasmolysis [6].Be Tropane alkaloids as clinic uses antispasmodic atropine, medication history for a long time, its
Spasmolysis mechanism is m receptor antagonism.But atropine to body of gland, smooth muscle, nervous system due to having effect, because
This has a variety of side effects while disease is treated, in contrast, the discovery of the m receptor antagonist of different structure, especially originally
Body is noval chemical compound, may there is smaller side effect.This patent is the hydroxy cinnamate amide-type for disclosing a kind of known structure
Compound, it is very big with known Tropane alkaloids architectural difference, result of study show the compound equally have preferable M by
Body antagonistic activity, imply that and be applied to clinic possibly as a kind of smaller spasmolysis medicine of side effect.
We apply high performance liquid chromatography preparing chromatography system, rp mode [7] from suitable Alkaloid separation and from
Sub- switch mode [8,9], prepares for the alkaloid in Anisodus tanguticus, obtains a kind of hydroxy cinnamate amide-type chemical combination
Thing.We establish the screening mould of muscarine m receptor antagonist using n cell target spot pharmacological techniques in early-stage Study
The antagonistic activity of alkaloid one-dimensional cut in type, and application model discrimination Anisodus tanguticus to muscarine m receptor.This
Invention carries out the screening of compound with the screening model for the m receptor antagonist having built up, it is found that this compound has for m receptor
Good antagonism, this [4] different from the action target spot that such compound has been reported may have before relatively good clinical practice
Scape.
Bibliography：
[1] 4 kinds of alkaloids and the research Chinese medicines of height above sea level relation in Wang Huan, Shen Jianwei, Zhang Xiaofeng Tangut Anisodus Radixs
Magazine, 2002,27 (2):151-152
[2] in the such as Zhang Xiaofeng Tangut Anisodus Radix plants 4 kinds of tropane alkaloidses contents change northwests Botany Gazette,
2002,22(3):630-634
[3] offer birthday congratulations Chinese Chinese and Western of discussion of effect and mechanism of the anisodamines such as river in fulminant type epidemic meningitis complex treatment
Curing binding can microcirculation Professional Committee first time Symposium Held, 1987.
[4]Long Z et.al.Amide alkaloids from scopolia tangutica.Planta med,
2014,80:1124-1130.
[5] the Chinese health nutrients of effect of the Zhang Cuiping simple analysis anticholinergic agentses in acute biliary colic treatment, 2013,
23(6):3277.
[6] Shi Yiming, button studies magazine because of Yao, Lu Yang .M acceptors and Correlation selection Research progress of drugs Inpharms,
2009,36(5):355-361.
[7]Zhimou Guo et.al.Polar-copolymerized approach based on horizontal
polymerization on silica
surface for preparation of polar-modified stationary phases.Journal
of Chromatography A,2010,1217:4555–4560.
[8]Long Z et.al.Selective separation and purification of highly polar
basic compounds using a silica-based strong cation exchange stationary
phase.Analytica Chimica Acta,2013,804:304-312.
[9]Long Z et.al.Two-dimensional strong cation exchange/positively
charged reversed-phase liquid chromatography for alkaloid analysis and
purification.J.Sep.Sci,2013,36,3845–3852。
The content of the invention
The present invention relates to the discovery of BDCS and its derivative action target spot in hydroxy cinnamate amides compound and suchization
The application of compound, the action target spot that the first purpose is to provide hydroxy cinnamate amides compound is muscarine m receptor；The second purpose
It is to provide the application of such compound clinically.
The technical scheme is that：
BDCS and its derivatives chemical structure are as follows：
One or both of corresponding pharmaceutically acceptable salt of muscarine m receptor the antagonist BDCS and BDCS
It is above active component, wherein can also add pharmaceutically acceptable carrier or excipient, such as：Starch, sodium chloride, microcrystalline cellulose
Element, sorbic acid and/or mannitol etc..The administering mode of said composition can be but not limited to intravenous administration, oral, muscle,
Subcutaneously, the mode such as skin surface, local injection is administered, and it is parenteral solution, freeze drying powder injection that its formulation, which can be, but not limited to, inject micro-
Ball, liposome, tablet, capsule, aqua, powder, paste, spray, granule, soft capsule, pill, gel, paster,
Paste etc., wherein it is preferred that parenteral solution, freeze drying powder injection, tablet and capsule, paster.
Hydroxy cinnamate amides compound of the present invention is preparing analgesia, spasmolysis, calmness, rescue organophosphorus poisoning etc.
Application in disease medicament, wherein hydroxy cinnamate amides compound are the corresponding pharmaceutically acceptable salts of BDCS and BDCS
One or both of more than.
The muscarine m receptor antagonist be with one or both of BDCS and BDCS pharmaceutically acceptable salts with
Upper is active component, wherein can also add pharmaceutically acceptable carrier or excipient.
BDCS and its derivative in the present invention act on muscarine m receptor, and this acceptor is g protein coupled receptor, with convulsion
The correlations such as contraction, calmness, parkinsonism, schizophrenia, depression, according to target spot and the correlation of disease, can widen this change
The clinical application range of compound.
The present invention is the discovery and application of the hydroxy cinnamate amides compound action target spot separated in a kind of plant of Solanaceae,
Specifically hydroxy cinnamate amides compound N1, N8-Bis (dihydrocaffeoyl) spermidine (abbreviation BDCS)
Action target spot discovery and spasmolysis medicine in application.The present invention is by using n cell target spot pharmacological techniques, hair
This existing compound has stronger muscarine m receptor antagonistic activity, and quantitative dose-effect relationship shows dose-dependently antagonism acetyl
DMR response signals caused by choline, it is muscarine m receptor antagonist to show BDCS.The muscarine m receptor antagonist is with BDCS
And more than one or both of BDCS pharmaceutically acceptable salts be active component.Current study show that muscarine m receptor
It is related to the disease such as spasm, analgesia, calmness, schizophrenia, action target spot can be provided for relevant disease accordingly clearly efficient
New part.
Brief description of the drawings
The purifying preparation process chromatogram of Fig. 1 compounds；
DMR caused by acetylcholine after DMR signals and m receptor the antagonist pretreatment of Fig. 2 muscarine m receptor antagonists
Signal：
A. after the henbane alkali process HT29 cells of various concentrations caused by DMR signals；
B. after the henbane oxygenation pretreatment HT29 cells of various concentrations, DMR signals caused by acetylcholine (16 μM) are added；
C. the hyoscine of various concentrations handles DMR signals caused by after HT29 cells；
D. after the hyoscine pretreatment HT29 cells of various concentrations, add DMR caused by acetylcholine (16 μM) and believe
Number；
DMR signals caused by acetylcholine after the BDCS of Fig. 3 various doses DMR signals and BDCS pretreatment；
Fig. 4 compounds BDCS locates the amount effect relation curve of DMR signals caused by dosage and 16 μM of acetylcholines in advance.
Embodiment
Following non-limiting examples can make one of ordinary skill in the art be more fully understood the present invention, but not with
Any mode limits the present invention.The present invention is further illustrated in the way of specific embodiment below.
Various chemical reagent used in the embodiment of the present invention are obtained by routine business approach unless otherwise specified
；Acetylcholine is purchased from lark prestige company；Anisodus tanguticus medicinal material is adopted by northwest plateau plant institute Qinghai, Tang Gute mountains Liang
Alkaloid compound in henbane is made by oneself by laboratory；DMSO is bought from Bio Basic companies；HBSS and McCoy ' s 5A cultures
Liquid is purchased from Gibco companies；384 hole biological inductor minitype plates are purchased from Corning companies；HT29 human colon cancer cells from
The American Type Culture Collection committee of Chinese Academy of Sciences cell bank is obtained (China, Shanghai).
In the Anisodus tanguticus of embodiment 1 prepared by the purifying of alkaloid compound
1. laboratory apparatus and reagent
Anisodus tanguticus medicinal material is adopted by northwest plateau plant institute Qinghai, is identified through teacher Mei Lijuan.Chromatographic column
XCharge C18 (4.6 × 250mm, 7 μm, Hua Pu companies), XCharge C18 (100 × 280mm, 7 μm, Hua Pu companies),
XCharge SCX (100 × 316mm, 7 μm, Hua Pu companies), XCharge C18 (20 × 250mm, 7 μm, Hua Pu companies), it is anhydrous
Sodium sulphate, two hypophosphite monohydrate sodium dihydrogens are purchased from Chinese medicines group, and monoethanolamine, phosphoric acid, formic acid is purchased from lark prestige, prepares chromatographic grade acetonitrile
Join during purchased from Anhui.
2. it is prepared by the purifying of compound
Anisodus tanguticus medicinal material 50kg is extracted with ethanol, is extracted in two batches, every crowd of 25kg, plus is added after the immersion of 80L ethanol
Heat backflow 2h, extracts three times, obtains 350L extract solutions.Extract solution is concentrated into 100L, with the SCX SPE materials of strong cation exchange
Enriched biological alkaline constituents, 1.5kg fillers, each loading concentrate 10L, methanol 10L washing non-alkaloids, 250mM NH4ClO4/
90% methanol 20L elutes alkaloid.Alkaloid eluate is evaporated, the molten 0.1%TFA/W to 6L of weight, carries out the one-dimensional of C18HCE
Prepare, using ACN-Na2SO4/W systems, 30min ACN 5%-15% collect retention time 23-25min cut F15 (systems
Standby chromatogram is Fig. 1 a), SCX two dimension preparation, ACN-30mM NaH are carried out to it2PO4- W, 30min ACN 35%-50%,
Retention time 33-35min chromatographic peak F15_2 (preparing chromatogram for Fig. 1 b) is collected, C18HCE 2%ACN-0.1% is carried out
Prepared by FA/W three-dimensionals, obtain F15_2_P4.The molecular ion peak m/z that cation ESI-MS is provided：474.0([M+H]+, molecular formula
C25H35N3O6, molecular weight 473.2).Nucleus magnetic hydrogen spectrum information is as follows：1H-NMR(D2O, 400MHz) δ:6.74(2H,d),6.67(1H,
s),6.65(1H,s),6.59(2H,d),3.08(2H,t),2.98(2H,t),2.70(4H,t),2.65(2H,t),2.45(4H,
t),2.40(2H,t),1.59(2H,m),1.24(4H,m).It is identified as known compound BDCS.
The DMR signal characteristics on Epic platforms of the muscarine m receptor antagonist of embodiment 2
1. method
1.1 cell culture
HT29 human colon cancer cells obtain from the American Type Culture Collection committee of Chinese Academy of Sciences cell bank (China, on
Sea).Hyclone of the HT29 cells containing volumetric concentration 10%, 50 μ g/ml ampicillins, 100 μ g/ml streptomycin sulphates
McCoy ' s 5A culture mediums (GIBCO, article No. 12800017,4500.0mg/L containing D-Glucose, add NaHCO32.2g/
L), in 37 DEG C, volume content 5%CO2Cultivated in the incubator of (air).
The cytoactive experimental method of 1.2 muscarine m receptor antagonists
HT29 cells are with 2 × 104The density in individual/hole is inoculated intoIn 384 hole biological inductor minitype plates, 37 are placed in
DEG C, volume content 5%CO222h is cultivated in the incubator of (air), is washed before detection with HBSS buffer solutions 1 time, then in every Kong Zhongjia
Enter 30 μ L HBSS buffer solutions, be placed inBalance is incubated 1h in system.Exist first after balanceOne is set up in system
2min baseline, then by hyoscyamine, the μ L of hyoscine 10, (each compound has 14 concentration points, the μ of highest working concentration 10
M, 2 times dilute step by step, 5 μM, 2.5 μM, 1.25 μM etc.) it is separately added into and has been inoculated with HT29 cellsThe biology sense of 384 holes
Answer in device minitype plate,60min is monitored in system, the DMR response curves of compound are obtained.Then acetylcholine is added
(16 μM) are continued to monitor 60min, obtain acetylcholine DMR response curves.It is by monitoring DMR response signals caused by acetylcholine
The no testing compound added when being pretreated suppresses the antagonistic activity to judge compound to muscarine m receptor.
1.3 data analysis
DMR data are recorded by Epic Imager softwares (Corning Incorporated, the U.S.), and through Imager Beta3.7 software (health
Ning companies, the U.S.) processing obtain.Statistical is carried out using Microsoft Excel 2010 and GraphPad Prism softwares
Analysis.All DMR signals are all obtained through blank correction.All data are from 2 independent experiments, every time 3 repetitions.
2. result
Handled respectively with the muscarine m receptor antagonist hyoscyamine or hyoscine of various concentrations after HT29 cells, both
Do not cause DMR response signals, see Fig. 2 a, 2c (the corresponding DMR curve co-insides of antagonist of various concentrations), 16 μM are added again
Acetylcholine (EC80), DMR response signals caused by acetylcholine are suppressed, and the higher inhibitory activity of concentration of antagonist is stronger,
In dose dependent, see Fig. 2 b, 2d (Antagonist concentration is diluted to 1.22nM from 10 μM step by step, corresponding DMR signal curves from
Under to upper arrangement).It follows that muscarine m receptor agonist character DMR spectrums do not cause DMR response signals in itself for antagonist,
DMR response signals caused by antagonism acetylcholine.
Embodiment 3BDCS is to muscarine m receptor antagonistic activity
Using the n cell target spot pharmacological techniques compound BDCS stronger to m receptor antagonistic activity in screening active ingredients
Further dose-effect relationship has been carried out to investigate.First, 10 μ L testing compounds are added and has been inoculated with HT29 cells384 holes
In biological inductor minitype plate (be the same as Example 2),60min is monitored in system, 10 μ L acetylcholines (16 are then added
μM) continue to monitor 60min.DMR signals caused by compound are mapped with action time, (compound concentration is from 100 μM by such as Fig. 3 a
24.4nM is diluted to step by step, corresponding DMR signal curves are arranged from top to bottom, and signal intensity is little)；With action time to
Two steps add DMR response signals mapping caused by after acetylcholine, and as a result such as Fig. 3 b, (compound concentration dilutes step by step from 100 μM
To 24.4nM, corresponding DMR signal curves are arranged from top to bottom).It can be seen that BDCS does not draw on HT29 cells
DMR signals are played, and it is in dose dependent, i.e. BDCS to pre-process dosage with adding DMR response signals caused by acetylcholine again
Concentration is higher, and inhibitory activity is stronger.This is consistent with the feature of muscarine m receptor antagonist, thus infers, BDCS is muscarine M
Receptor antagonist.
In second step lab diagram, the acetylcholine DMR signals at compound BDCS each concentration 30min time points are chosen
Value, using log concentration as abscissa, DMR values are ordinate, and antagonistic activity curve is fitted in prism softwares, compound is obtained
BDCS IC50Value, is shown in Fig. 4.
Claims (7)
1. a kind of compound, it is N1, and N8-Bis (dihydrocaffeoyl) spermidine, is hydroxy cinnamate amide-type
Compound, hereinafter referred to as BDCS, with following structural formula：
2. a kind of muscarine m receptor antagonist, it is characterised in that：The muscarine m receptor antagonist is described in claim 1
It is more than one or both of BDCS and BDCS pharmaceutically acceptable salts.
3. a kind of muscarine m receptor antagonist composition, it is characterised in that：The muscarine m receptor antagonist is will with right
It is active component to ask more than one or both of BDCS and BDCS pharmaceutically acceptable salts described in 1, wherein can also add
More than one or both of pharmaceutically acceptable carrier or excipient.
4. a kind of application of hydroxy cinnamate amides compound in spasmolysis medicine is prepared, it is characterised in that：Hydroxy cinnamate acid amides
Class compound is included more than one or both of BDCS and BDCS pharmaceutically acceptable salts described in claim 1, its
Spasmolysis mechanism is muscarine m receptor antagonistic activity.
5. according to the application described in claim 4, it is characterised in that：Described spasmolysis medicine is included described in claim 1
More than one or both of BDCS and BDCS pharmaceutically acceptable salts it is active component, wherein may further be enriched with pharmaceutically
It is more than one or both of acceptable carrier or excipient.
6. a kind of application of hydroxy cinnamate amides compound in muscarine m receptor antagonistic activity medicine is prepared, its feature exists
In：Hydroxy cinnamate amides compound includes one in BDCS the and BDCS pharmaceutically acceptable salts described in claim 1
Plant or two or more.
7. according to the application described in claim 6, it is characterised in that：Described spasmolysis medicine is included described in claim 1
More than one or both of BDCS and BDCS pharmaceutically acceptable salts it is active component, wherein may further be enriched with pharmaceutically
It is more than one or both of acceptable carrier or excipient.
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Cited By (3)
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| CN109810014A (en) * | 2017-11-20 | 2019-05-28 | 中国科学院大连化学物理研究所 | A kind of two caffeoyl spermidine class compound selective enrichment methods in fructus lycii |
| CN112730821A (en) * | 2019-10-14 | 2021-04-30 | 泰州医药城国科化物生物医药科技有限公司 | Method for analyzing long-acting property of receptor antagonist |
| CN112898214A (en) * | 2019-12-04 | 2021-06-04 | 中国科学院大连化学物理研究所 | Cyclic cinnamide compound and preparation method and application thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109810014A (en) * | 2017-11-20 | 2019-05-28 | 中国科学院大连化学物理研究所 | A kind of two caffeoyl spermidine class compound selective enrichment methods in fructus lycii |
| CN109810014B (en) * | 2017-11-20 | 2022-03-08 | 中国科学院大连化学物理研究所 | Method for selectively enriching dicaffeoylspermidine compounds in fructus lycii |
| CN112730821A (en) * | 2019-10-14 | 2021-04-30 | 泰州医药城国科化物生物医药科技有限公司 | Method for analyzing long-acting property of receptor antagonist |
| CN112730821B (en) * | 2019-10-14 | 2024-04-09 | 泰州医药城国科化物生物医药科技有限公司 | Method for analyzing long-acting property of receptor antagonist |
| CN112898214A (en) * | 2019-12-04 | 2021-06-04 | 中国科学院大连化学物理研究所 | Cyclic cinnamide compound and preparation method and application thereof |
| CN112898214B (en) * | 2019-12-04 | 2022-07-19 | 中国科学院大连化学物理研究所 | Cyclic cinnamide compound and preparation method and application thereof |
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