CN104721180B - Application of the jatamans valeriana rhizome iridoid position in preparing N-type ockers - Google Patents
Application of the jatamans valeriana rhizome iridoid position in preparing N-type ockers Download PDFInfo
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Abstract
The invention discloses a kind of application of jatamans valeriana rhizome iridoid position in preparing N type ockers, belong to drug field.The present invention provides effect of the jatamans valeriana rhizome iridoid position in the inhibition of N type calcium channels, and confirm in jatamans valeriana rhizome iridoid position and inhibit the two kinds of iridoid ingredients to play a role to N type calcium channels；The present invention is also found that inhibition of the Acidic Hydrolysis Products in N type calcium channels of iridoid for the first time；Therefore the present invention provides jatamans valeriana rhizome iridoid positions as a kind of broad prospect of application of new N type ockers, can apply to the treatment of the relevant diseases such as pain.
Description
Technical field：
The invention belongs to drug field, more particularly to a kind of jatamans valeriana rhizome iridoid position is preparing the inhibition of N-type calcium channel
Application in agent.
Background technology：
N-type voltage-dependent ca channels are distributed mainly on the neuronal synapse tip of pain transmission and regulatory pathway, ginseng
With the release and adjusting of pain mediator (such as glutamic acid and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2), is transmitted in pain and play an important roll (state in regulation process
Outer medicinal pharmacology fascicle, 34 (2), 93-98).Therefore, block N-type calcium channel that can generate analgesic activity, especially chronic pain
Pain and neurogenic pain.Though can be relieved pain using opioid drug, there are the secondary works such as respiration inhibition, constipation and habituation
With.Therefore, finding the new type analgesic object of analgesic activities height and Small side effects has become project of people's attention.N-type calcium is logical
Road is suppressed, and norepinephrine secretion is reduced, intestinal smooth muscle diastole, mesenteric diastole, can be played slow well
Solve abdominal pain.
Jatamans valeriana rhizome is rhizome also known as the horse of Valerianaceae valerian jatamans valeriana rhizome Valeriana jatamansi Jones
Hoof perfume, Devil Frown, beans dish root, nine turns of perfume (or spice), Herba clintoniae udensis, small RHIZOMA ET RADIX VALERIANAE JATNANSI, smelly dog medicine, mill pin flower, Lao Longxu, vanilla, blood-nourishing lotus,
Smelly medicine Sea Cucumber, is rescued greatly, tiger seven etc..Jatamans valeriana rhizome is herbaceos perennial, is mainly distributed on Southwestern China area, resource
It is abundant,《Chinese Pharmacopoeia》Versions in 1977 and version in 2010 are included, and have regulating qi-flowing for relieving pain, the antidiarrheal that helps digestion, dispelling wind and eliminating dampness, calmness
The effect of tranquilizing the mind, is usually used in abdomen gastral cavity distending pain, accumulation of food in the stomach and intes tine due to indigestion, diarrhea dysentery, arthralgia pain due to rheumatism, soreness and weakness of waist and knees, insomnia etc..Jatamans valeriana rhizome is made
For traditional medicinal plant, in addition to Han nationality, such as covers in many minority areas in China, hides, seedling, dimension also have long application
History (CHINA JOURNAL OF CHINESE MATERIA MEDICA, 37 (4), 2174-2177).
The chemical research of jatamans valeriana rhizome the result shows that, main chemical compositions are iridoids, volatile oil, flavones etc..Its
Middle cyclenes ether ter penoids are main active constituents in jatamans valeriana rhizome, and forefathers report that this kind of compound has for example anti-coke of CNS inhibition
Consider, antidepressant effect, calm, hypnosis and analgesic activity etc..There are heart inhibiting effect, improvement intestines easy in addition, jatamans valeriana rhizome is also reported
Swash effect etc..But these results of study of forefathers carry out still the research of the specific mechanism of action of jatamans valeriana rhizome and relevant disease
It is few, carry out the hydrolysis of jatamans valeriana rhizome active site and the report for obtaining active site is less.For this purpose, invention mainly encloses
Around jatamans valeriana rhizome active constituent type, activated monomer and sour water solution Rhizoma valerianae latifoliae extract and obtain that there is inhibition N-type calcium channels
The expansion description of active pharmaceutical position.
Invention content：
It is an object of the invention to overcome shortcoming and deficiency existing in the prior art, a kind of jatamans valeriana rhizome iridoid is provided
Application of the position in preparing N-type ockers.
Another object of the present invention is to provide application of the jatamans valeriana rhizome iridoid position acid hydrolysis products in pharmacy.
The purpose of the invention is achieved by the following technical solution：Jatamans valeriana rhizome iridoid position is preparing the suppression of N-type calcium channel
Application in preparation.
The jatamans valeriana rhizome iridoid position includes the iridoid constituents as shown in formula I, the iridoid
Constituents account for 30% or more jatamans valeriana rhizome iridoid portion gross mass；
Wherein, R1, R3 are isovaleryl or substitution isovaleryl, and R2, R4 are isovaleryl, substitution isovaleryl, acetyl
Base, propiono, bytyry, substitution acetyl group, substitution propiono or substitution bytyry；
The substituent group replaced described in isovaleryl, substitution acetyl group, substitution propiono and substitution bytyry
For one kind in H, acetyl group, propiono, bytyry or isovaleryl.
The iridoid constituents include valtrate hydrine B8 shown in formula II；
The iridoid constituents include valeriandoid J shown in formula III；
The jatamans valeriana rhizome iridoid position is preferably obtained by following preparation method：Jatamans valeriana rhizome alcohol reflux is percolated,
Recycling ethyl alcohol obtains aqueous suspension, then is concentrated to give jatamans valeriana rhizome iridoid position with ethyl acetate extraction, and iridoid constituents account for
30% or more gross mass.
The jatamans valeriana rhizome iridoid position is obtained preferably by preparation method in detail below：Take jatamans valeriana rhizome medicinal material powder
1000 grams of end is added 95% ethyl alcohol 3500ml and sets the 3h that flows back in reflux, ethanol is filtered out after cooling, and ethyl alcohol is added in residue
3000ml flows back 2h again, filters out ethanol extract and is merged into first time ethanol filtrate, obtains ethanol extract about 6000ml, dense
Contracting ethanol extract is added ethyl acetate and extracts to obtain jatamans valeriana rhizome iridoid position, iridoid constituents account for aqueous suspension
30% or more gross mass.
The jatamans valeriana rhizome derives from the dry rhizome of patrinia herb jatamans valeriana rhizome Valeriana jatamansi Jones
And root.
As preferred embodiment, the jatamans valeriana rhizome iridoid position is produced by the sour water solution of iridoid position
Object is applied.
The acid is hydrochloric acid.
Application of the jatamans valeriana rhizome iridoid position acid hydrolysis products in pharmacy.
The present invention has the following advantages and effects with respect to the prior art：
The present invention provides a kind of effect of jatamans valeriana rhizome iridoid position in the inhibition of N-type calcium channel, and confirm spider
The two kinds of iridoid ingredients to play a role are inhibited to N-type calcium channel in spider perfume (or spice) iridoid position；The present invention also has found for the first time
Inhibition of the Acidic Hydrolysis Products of iridoid in N-type calcium channel；Therefore the present invention provides jatamans valeriana rhizome iridoids
Position can apply to the treatment of the relevant diseases such as pain as a kind of broad prospect of application of new N-type ockers.
Specific implementation mode：
With reference to embodiment, the present invention is described in further detail, and embodiments of the present invention are not limited thereto.
Embodiment 1：
A kind of preparation method of jatamans valeriana rhizome iridoid position is present embodiments provided, steps are as follows：Take jatamans valeriana rhizome medicinal material
1000 grams of powder is added 95% ethyl alcohol 3500ml and sets the 3h that flows back in reflux, ethanol is filtered out after cooling, and ethyl alcohol is added in residue
3000ml flows back 2h again, filters out ethanol extract and is merged into first time ethanol filtrate, obtains ethanol extract about 6000ml, dense
Contracting ethanol extract is added ethyl acetate and extracts to obtain jatamans valeriana rhizome iridoid position to aqueous suspension, the jatamans valeriana rhizome iridoid
Position can effectively inhibit N type calcium channels.Suitable vehicle, adhesive, disintegration is added in the jatamans valeriana rhizome iridoid position
Agent is tabletted, obtains 1000, tablet.
Embodiment 2：
A kind of hydrolysate acquisition methods of iridoid position are present embodiments provided, are as follows：Above-mentioned reality
Gained jatamans valeriana rhizome iridoid position in example 1 is applied, the aqueous hydrochloric acid solution 1000ml that 0.01M is added is miscible, and Stirring reacts 1h,
It is neutralized to pH=7 with the NaOH of 0.01M after stopping reaction, then is extracted with ethyl acetate, the water of iridoid position is concentrated to give
Product is solved, which can effectively inhibit N type calcium channels.
Embodiment 3：
The active material identification verification of jatamans valeriana rhizome iridoid position in embodiment 1
Gained jatamans valeriana rhizome iridoid position, takes 50g to mix sample with 100g silica gel (200-300 mesh) in above-described embodiment 1, on
10 times of amount silicagel columns (0.5kg, 200-300 mesh), mobile phase is petroleum ether:Acetone=50:1~0:1, elute to obtain 7 component (Fr
1-7).Component 4 (Fr.4,2.8g) continues with silica gel column chromatography (petroleum ether：Acetone=20:1~1:1 gradient elution), obtain 4 groups
Part (Fr.4.1~4.4 sub).Wherein second inferior component (sub Fr.4.2,0.8 gram) is through MCI glue (60%~90% methanol
Gradient elution), gel sephadex LH-20 (methanol), reverse phase ODS (methanol:Water=50:50~90:10) purifying obtains chemical combination
Object valeriandoid B8 (compound 1, as shown in formula II, 5mg).Component 6 (Fr.6,5.3g) is obtained with approximation method
Valtrate hydrine J (compound 2, as shown in formula III, 0.23 gram).The two iridoid monomers have good N
Type calcium channel inhibitory activity.
Embodiment 4：
Examples 1 to 3 obtains the N-type calcium channel inhibitory activity verification of product.
The acid hydrolysis products of jatamans valeriana rhizome iridoid position, iridoid position that Examples 1 to 3 is obtained and separation
(valtrate hydrine J, are abbreviated as obtained compound 1 (valeriandoid B8, be abbreviated as zjv27) and compound 2
Zjv31 the screening of N type calcium channel inhibitory activity) is carried out, acquired results are as shown in table 1：
The N-type calcium channel inhibitory activity testing result of 1 each extract of table
| Number | Title | Concentration | Inhibiting rate |
| 1 | Jatamans valeriana rhizome iridoid position | 0.01mg/ml | 35% |
| 2 | The acid hydrolysis products of iridoid position | 0.01mg/ml | 84% |
| 3 | Valeriandoid B8 (compound 1) | 10um | 48% |
| 4 | Valtrate hydrine J (compound 2) | 10um | 47% |
It can be seen from result in table 1 jatamans valeriana rhizome iridoid position, iridoid position acid hydrolysis products and point
Higher inhibitory activity is all had to N-type calcium channel from obtained compound 1 and compound 2, wherein iridoid position
The inhibitory activity of acid hydrolysis products is high, reaches 84% inhibiting rate.
By gained jatamans valeriana rhizome iridoid position, acid hydrolysis products and isolated compound zjv27 and zjv31 into
Row N type calcium channel inhibitory activity is screened, and experimentation is as follows：
It is prepared by frog's egg：
At ambient temperature, the abdomen middle and lower part of Africa xenopus is dissected, ovary is taken out, and be cut into the fritter of 4~4mm, is put in
OR2 (82.4mM NaCl, 2.5mM KCl, 1mM MgCl2, and 5mM hepes, PH 7.6with NaOH) is containing certain dense
The Collagenase A of degree digests 2~3h with the speed of 180rmp on subsequent shaking table, obtains the independent IV- for eliminating vitellinae membrana
V phases uniform frog's egg, with ND96 (96mM NaCl, 2.5mM KCl, 1mM MgCl2,5mM Hepes, 1.8mM CaCl2,
100 μ g/mL streptomycin, pH 7.6with NaOH of 100units/mL penicillin, and) it cleans in liquid, and
It is put in 18 DEG C of constant incubators for use.
The injection and culture of mRNA：
Synthesize the mRNA of N type calcium channels in vitro by molecular biology method, then utilize microinjection instrument with
The injection volume of 50.6nl is injected into frog's egg, and is put in 18 ° of incubators and is cultivated 3~4 days.
The active testing of compound and primary extract：
After culture 3~4 days, there is the electric current of N type calcium channels to express on frog's egg cell membrane, utilize Two-electrode voltage-clamp
Test the effect of compound and primary extract to N type calcium channels.Test is as follows：
1, under conditions of room temperature, ovum is placed in test bath, by voltage electrode and galvanic electrode gently rupture of membranes insertion
Frog's egg causes electrode to be communicated with frog's egg cytoplasm.Wherein the resistance of electrode is between 0.3~1 megaohm.Record N is put into bath
Barium ions solution (50mM NaOH, 2mM KCl, 5mM Hepes, 1.8mM the BaCl2,40mM Ba (OH) 2. of type calcium channels
With Loprazolam tune pH to 7.4, solution uses after need to filtering.)
2, it quickly clamps down on, Clamping voltages are -80mv, sample frequency 10kHz, low frequency filtering 10kHz, recording voltage -
30mv to 70mv, is divided into 10mv, when record a length of 50ms, obtain N type Calcium Currents.
3, jatamans valeriana rhizome iridoid position, 0.01mg/ are obtained after primary extract ethyl alcohol being extracted and is extracted with ethyl acetate
Ml is 48% to inhibiting rate of the N type calcium channels in 20mv；By iridoid position with obtaining sour water solution after HCl/water solution 1h
Product, 0.01mg/ml are 67% to inhibiting rate of the N type calcium channels in 20mv.
4, two isolated compound zjv 27 and zjv 31 divide the inhibiting rate of N type calcium channels at 10 μM
It Wei 48% and 47%.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, it is other it is any without departing from the spirit and principles of the present invention made by changes, modifications, substitutions, combinations, simplifications,
Equivalent substitute mode is should be, is included within the scope of the present invention.
Claims (3)
1. applications of the valtrate hydrine B8 in preparing analgesic shown in Formula II,
2. applications of the valeriandoid J in preparing analgesic shown in formula III,
3. application of the jatamans valeriana rhizome iridoid position acid hydrolysis products in preparing analgesic, it is characterised in that the spider
Fragrant iridoid position acid hydrolysis products are prepared by following methods：Jatamans valeriana rhizome is percolated through 95% alcohol reflux, ethyl alcohol extraction
Liquid is concentrated into aqueous suspension, then extracts to obtain jatamans valeriana rhizome iridoid position with ethyl acetate, and the aqueous hydrochloric acid solution that 0.01M is added is mixed
Molten, Stirring reacts 1h, stops being neutralized to pH=7 with the NaOH of 0.01M after reacting, then extract with ethyl acetate, concentrate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101444501A (en) * | 2008-12-25 | 2009-06-03 | 中国人民解放军第二军医大学 | Application of mother-nucleus conjugated iridoid in preparing anti-tumor medicine |
| CN103599144A (en) * | 2013-10-22 | 2014-02-26 | 浙江中医药大学 | Preparation method for effective part of valerianajatamansi epoxy iridoid ester |
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2015
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101444501A (en) * | 2008-12-25 | 2009-06-03 | 中国人民解放军第二军医大学 | Application of mother-nucleus conjugated iridoid in preparing anti-tumor medicine |
| CN103599144A (en) * | 2013-10-22 | 2014-02-26 | 浙江中医药大学 | Preparation method for effective part of valerianajatamansi epoxy iridoid ester |
Non-Patent Citations (3)
| Title |
|---|
| Acylated Iridoids with Cytotoxicity from Valeriana jatamansi;Sheng Lin等;《J. Nat.Prod.》;20090226;第72卷;650-655 * |
| N型钙通道在大鼠福尔马林内脏炎性症痛中的作用研究;张颜波 等;《中国疼痛医学杂志》;20081231;第14卷(第4期);230-232 * |
| 蜘蛛香环烯醚萜对肠易激综合征的治疗作用及机理探讨;闫兴丽;《中国博士学位论文全文数据库 医药卫生科技辑》;20091115(第11期);E056-59 * |
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