CN106432160A - Phenylpropanoid compound and preparation method and application thereof - Google Patents
Phenylpropanoid compound and preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
- C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
Abstract
The invention provides a phenylpropanoid compound in acorus calamus and a preparation method and application thereof. The compound is obtained through separation and purification of (R)-1,2-split-ring ceplignan, (2S,3R)-ceplignan and (2R,3S)-ceplignan from acorus gramineus rhizomes, has 5-hydroxytryptamine transporter (SERT) adjusting activity, can be applied to preparation of drugs for resisting depression, anxiety disorder, schizophrenia, obsessive-compulsive disorder neurodegeneration and other diseases and preparation of drugs for treating drug addiction, digestive system dysfunction and other diseases, and has important drug development value.
Description
Technical field
The present invention relates to Chinese medicine research field, especially phenylpropanoids and preparation method and application.
Background technology
5-hydroxy tryptamine transporter (SERT) is a kind of transmembrane transporter having high affinity to 5-HT,
Containing about 630 amino acid residues, its encoding gene (SLC6A4) is located at No. 7 and No. 11 chromosomes respectively
On, it is made up of 14 exons that span is about 35kb.SERT albumen comprises 12-13 transmembrane region,
N-terminal and C-terminal are located in kytoplasm, have cAMP deopendent protein kinase binding site at N-terminal, the
Have one to be located at extracellular annulus between three and the 4th transmembrane region, be the glycosylation site that N- connects.
SERT belongs to Na+/Cl-Dependent form transport protein, is predominantly located at 5-HT serotonergic neuron.SERT from
Reuptake 5-HT in nerve synapse gap and enter presynaptic neuron, directly affect synaptic space 5-HT
Concentration, changes amount and the acting duration that postsynaptic receptor mediates signal.It moreover has been found that SERT is in tire
Disk tissue, bone marrow, kidney, lung, the heart, adrenal gland, liver, parathyroid gland, thyroid, pancreas and small intestinal
Also it is distributed in organ, point out SERT to participate in different physiological roles.
SERT is the important molecule of transhipment 5-HT, is permitted with emotion, appetite, sleep, memory, study etc.
Many Physiological Psychologies function is related, SERT and 5-HT expression change can cause anxiety, depression, obsession, fear
Fear disease, or even schizophrenia, and closely related with drug addiction；It moreover has been found that SERT is in gastrointestinal
Play key player in road functional disease, such as clinically slow Constipation, irritable bowel syndrome,
The functional gastrointestinal diseases such as functional distension, obtain using for the antidepressants of SERT, anxiolytic drugs
Curative effect.
SERT is the important target spot of clinical medicine research and development, selective serotonin reuptake depressant (SSRI)
Including fluoxetine, paroxetine, Sertraline, fluvoxamine, citalopram etc., clinic is usually used in treating
Depression, anxiety neurosis and obsession etc., such medicine sedation is little, does not also damage Psychomotor ability,
Very little is affected on cardiovascular and autonomic nervous system function.
Rhizoma Acori Graminei Acorus tatarinowii is Acorus of Araceae plant, has removing dampness to restore normal function of the stomach, opens
Key eliminating phlegm, refreshment effect of benefiting intelligence, Rhizoma Acori Graminei it has been reported that biological activity include (1) and act on nerveous system
System, such as antidepressant, calm and convulsion, brain protection and Fructus Alpiniae Oxyphyllae, (2) act on cardiovascular system, such as
Lipid-loweringing and decreasing heart rate, (3) act on respiratory system, such as treatment chronic bronchitiss, bronchial asthma,
(4) antibacterial, (5) anticancer etc.；The chemical composition of Rhizoma Acori Graminei includes volatile oil, lignanoid, phenolic acid, life
Alkaloids, flavone etc., and in terms of active material base, volatile ingredient report is more, non-volatile
Composition is rarely reported.
Content of the invention
The technical problem to be solved is to provide phenylpropanoids.
Another technical problem to be solved by this invention is to provide the preparation side of above-mentioned phenylpropanoids
Method.
Another technical problem to be solved by this invention is to provide the application of above-mentioned phenylpropanoids.
For solving above-mentioned technical problem, the technical scheme is that：
Phenylpropanoids, have following structural formula (I) formula：
Wherein, A is (R) -1,2- driffractive ring Ceplignan
{4-hydroxy-3-[1-hydroxy-3-(4-hydroxy-3-methoxyphenyl)
Propan-2-yl] -5-methoxy benzoic acid, A, B be (2S, 3R)-Ceplignan [(2S,
3R)-ceplignan, B], C is (2R, 3S)-Ceplignan [(2R, 3S)-ceplignan, C].
Preferably, above-mentioned phenylpropanoids, its physical chemistry and Spectroscopic Properties are：
(R) -1,2- driffractive ring Ceplignan
{4-hydroxy-3-[1-hydroxy-3-(4-hydroxy-3-methoxy phenyl)
Propan-2-yl] -5-methoxybenzoic acid, A }, white amorphous powder (methanol), 254nm
There are skin dark stain, unstressed configuration under 365nm uviol lamp under uviol lamp.(c 0.23,MeOH)；UV
(MeOH)λmax:268nm；CD(MeOH,c 0.1)λ(Δε):213(-1.17),283(-0.13)
nm；1H-NMR and13C-NMR data is shown in specific embodiment part table 1；HR-ESIMS m/z 347.1124
[M-H]-(347.1136calcd for C18H19O7 -).(+)-ESIMS m/z 349.34[M+H]+,
(-)-ESIMS m/z 347.09[M-H]-.
(2S, 3R)-Ceplignan [(2S, 3R)-ceplignan, B], white amorphous powder (methanol),
There are skin dark stain, unstressed configuration under 365nm uviol lamp under 254nm uviol lamp.(c 0.2,MeOH)；
UV(MeOH)λmax:275nm；CD(MeOH,c 0.055)λ(Δε):263(+2.77),294
(+2.10)nm；1H-NMR and13C-NMR data is shown in specific embodiment part table 2；(+)-ESIMS m/z
347.54[M+H]+,(-)-ESIMS m/z 345.18[M-H]-.
(2R, 3S)-Ceplignan [(2R, 3S)-ceplignan, C], white amorphous powder (methanol),
There are skin dark stain, unstressed configuration under 365nm uviol lamp under 254nm uviol lamp.(c 0.16,MeOH)；
UV(MeOH)λmax:275nm；CD(MeOH,c 0.055)λ(Δε):261(-1.03),295
(-1.07)nm；1H-NMR and13C-NMR data is shown in specific embodiment part table 2.
The preparation method of above-mentioned phenylpropanoids, comprises the following steps that：
(1) every 20kg Rhizoma Acori Graminei rhizome is boiled 3 times with the decocting of 8,6,6 times of weight respectively, and 1.5 is little every time
When, united extraction liquid, it is evaporated to the 1/5-1/10 of extracting liquid volume, obtain crude extract concentrated solution；
(2) gained crude extract concentrated solution, through D101 macroporous resin column chromatography, alcohol-water (v/v) gradient
Eluting, obtains 30%, 50%, 70%, 95%4 ethanol elution things, decompression and solvent recovery is to no alcohol respectively
Taste；
(3) adjust pH=3-4 with formic acid after 30% ethanol elution thing moisture being dissipated, equal-volume n-butyl alcohol extracts
Take 3 times, recycling design obtains n-butanol layer extractum；
(4) n-butanol layer extractum is through ODS column chromatography, methanol-water (v/v) gradient elution,
Collect 50% methanol water elution stream part, gained flow point is through Sephadex LH-20 gel column 50% methanol-water
(v/v) 9 components are separated to obtain, wherein component SDB4-3 is molten through silica gel G column chromatography, methylene chloride-methanol
Agent gradient elution, gained dichloromethane：Methanol volume ratio 15:1 eluting stream part is again through Semi-preparative High Performance
Liquid chromatograph separates and obtains (R) -1,2- driffractive ring Ceplignan
{4-hydroxy-3-[1-hydroxy-3-(4-hydroxy-3-methoxy phenyl)
Propan-2-yl] -5-methoxybenzoic acid, A }；
Collect 20% methanol water elution stream part, gained flow point is through Sephadex LH-20 gel column 50% methanol-water
(v/v) 5 components are separated to obtain, wherein component SDB2-4 separates through semipreparative high performance liquid chromatography and obtains
(2S, 3R)-Ceplignan [(2S, 3R)-ceplignan, B] and (2R, 3S)-Ceplignan [(2R,
3S)-ceplignan, C].
Above-mentioned phenylpropanoids are in terms of preparation adjusts 5-hydroxy tryptamine transporter (SERT) active medicine
Application.
Preferably, above-mentioned phenylpropanoids prepare depression, anxiety neurosis, schizophrenia,
The curative of the diseases such as obsession, neurodegenerative diseases, drug addiction or digestive system function disorder
The application in object space face.
There is the pharmaceutical composition of above-mentioned phenylpropanoids, comprise the benzene for the treatment of and/or prevention effective dose
Third chlorins compound and optional pharmaceutically acceptable excipient.
Above-mentioned pharmaceutically acceptable excipient can be any conventional excipient in field of pharmaceutical preparations, special
The selection determining excipient will depend upon administering mode or disease type and state for treating particular patient,
For specific administration pattern said synthetic processes preparation method completely drug world technical staff's
In the ken.For example, it is possible to include the conventional dilution of pharmaceutical field as pharmaceutically acceptable excipient
Agent, carrier, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant,
Absorption carrier and lubricant etc., if necessary, can also add flavouring agent, preservative in pharmaceutical composition
With sweeting agent etc..
Aforementioned pharmaceutical compositions can make tablet, powder, granule, capsule, oral liquid, unguentum,
The various ways such as cream, injectable emulsion, aseptic powder needle for injection, the medicine of various dosage forms all can be according to
The conventional method preparation of pharmaceutical field.
The invention has the beneficial effects as follows：
Phenylpropanoids of the present invention, from Acorus of Araceae plant Rhizoma Acori Graminei Acorus
Isolate and purify in the rhizome of tatarinowii and obtain, there is regulation 5-hydroxy tryptamine transporter (SERT) activity
Effect, can as depression, anxiety neurosis, schizophrenia, obsession, neurodegenerative diseases,
The medicine of the disease such as drug addiction and digestive system function disorder, has important drug development valency
Value.
Brief description
Fig. 1 is the related figure of crucial NOESY of phenylpropanoids in Rhizoma Acori Graminei；
Fig. 2 is the adjustment effect to SERT activity for the phenylpropanoids in Rhizoma Acori Graminei, wherein, positive control drug
2 M Fluoxetine and 1 M Tianeptine, * * p<0.01, * * * p<0.001；
Fig. 3 is compound (R) -1,2- driffractive ring Ceplignan1H-NMR and13C-NMR spectrogram；
Fig. 4 is compound (2S, 3R)-Ceplignan1H-NMR and13C-NMR spectrogram；
Fig. 5 is compound (2R, 3S)-Ceplignan1H-NMR and13C-NMR spectrogram；
Fig. 6 is the CD spectrogram of compound (2S, 3R)-and (2R, 3S)-Ceplignan.
Specific embodiment
In order that those skilled in the art is better understood from technical scheme, below in conjunction with the accompanying drawings
And specific embodiment is described in further detail to technical scheme of the present invention.
Experimental apparatus and reagent：Fourier transform nuclear magnetic resonance spectrometer (Bruker company of Switzerland, AVIII
Type 400MHz and 600MHz)；Developer：10% sulphuric acid ethanol.
Embodiment 1
The preparation (extraction separation process) of active component phenylpropanoids
Rhizoma Acori Graminei pharmaceutical decocting piece is purchased from Anhui Jiren Pharmacy Co., Ltd.'s (lot number：120519, specification：1kg/
Bag, the place of production：Anhui), about 20kg, decocted 3 times with 8,6,6 times of water yields respectively, each 1.5h,
United extraction liquid, recovered under reduced pressure to small size (80L), through D101 macroporous resin column chromatography, second after filtration
Alcohol-water (v/v) gradient elution, decompression and solvent recovery, obtain 30%, 50%, 70%, 95%4 ethanol
Eluate.
30% ethanol elution thing moisture adjusts pH=3-4 with formic acid after dissipating, equal-volume n-butanol extraction 3 times,
Butanol extraction liquid decompression and solvent recovery is taken to obtain dry extract, through ODS column chromatography (methanol-water ladder after water dissolution
Degree eluting), obtain 6 components, wherein 50% methanol-water eluate is through Sephadex LH-20 gel column 50%
Methanol-water (v/v) separate to obtain 9 components, wherein component SDB4-3 through silica gel G column chromatography (dichloromethane-
Methanol solvate gradient elution), gained dichloromethane：Methanol (15:1 (v/v)) make again by warp half for eluting stream part
Standby type high performance liquid chromatography separation obtains (R) -1,2- driffractive ring Ceplignan
{4-hydroxy-3-[1-hydroxy-3-(4-hydroxy-3-methoxyphenyl)
Propan-2-yl] -5-methoxy benzoic acid, A } (2.3mg)；Collect 20% methanol water elution
Stream part, gained flow point separates to obtain 5 components through Sephadex LH-20 gel column 50% methanol-water (v/v),
Wherein component SDB2-4 through semipreparative high performance liquid chromatography separate obtain (2S, 3R)-Ceplignan [(2S,
3R)-ceplignan, B] (2.3mg) and (2R, 3S)-Ceplignan [(2R, 3S)-ceplignan,
C](2.5mg).
Above-mentioned (R) -1,2- driffractive ring Ceplignan (A, Fig. 1), white amorphous powder (methanol), 254
There are skin dark stain, unstressed configuration under 365nm uviol lamp under nm uviol lamp.ESI-MS is respectively in m/z：349.34、
[M+H] is given at 347.09+Peak and [M-H]-Peak, in conjunction with table 1, Fig. 31H-NMR、13C-NMR compose to
The information going out, determines that molecular formula is C18H20O7.
1H-NMR low field area provides 5 fragrant Hydrogen Proton signals：Phenyl ring meta hydrogen signal δH7.29 (H-4),
The Hydrogen Proton signal δ of 7.42 (H-6) and ABX couplingH6.61(H-2')、6.57(H-5')、6.47
(H-6')；There is 1 methine Hydrogen Proton signal δ in high field regionH3.40 (H-7), 4 methylene hydrogen matter
Subsignal δH, in prompting structure, there is aliphatic chain in 3.48,3.56 (H-7), 2.74,2.95 (H-8)；
δH3.81st, 3.64 is the methoxyl group Hydrogen Proton signal on two phenyl ring.13C-NMR spectrum provides 18 carbon altogether
Signal, wherein high field region δC42.4 (C-7), 35.9 (C-9), 63.5 (C-8) are 1 methine
With 2 mesomethylene carbon signals, δC55.3rd, 55.7 is two methoxyl group carbon signals, and low field area gives in addition
2 groups of phenyl ring carbon signal δ are gone outC128.9(C-1)、148.5(C-2)、146.7(C-3)、109.8(C-4)、
122.9 (C-6) and 131.3 (C-1'), 113.0 (C-2'), 147.0 (C-3'), 144.3 (C-4'),
115.0(C-5')、120.9(C-6')；δC167.7 being carboxyl carbon signal.
As shown in figure 1, the HMBC spectrum of compound A has many places C-H related：Methylene Hydrogen Proton signal δH
2.47,2.95 (H-9) and carbon signal δC131.3(C-1')、113.0(C-2')、120.9(C-6')
There is correlation thus it is speculated that it is connected with one of structure phenyl ring；Methine Hydrogen Proton signal δH3.40(H-7)
With carbon signal δC128.9 (C-1), 148.5 (C-2), 122.9 (C-6) there is correlation thus it is speculated that its
It is connected with another phenyl ring in structure；And methylene Hydrogen Proton signal δH2.47th, 2.95 (H-9) with
Carbon signal δCThere is correlation in 128.9 (C-1), 42.4 (C-7), 63.5 (C-8), can speculate two
Phenyl ring is connected by 1 methylene and 1 methine, methoxyl group Hydrogen Proton signal δ simultaneouslyH3.81、
3.64 respectively with carbon signal δCThere is correlation, phenyl ring meta 2 in 146.7 (C-3), 147.0 (C-3')
Hydrogen signal δH7.29 (H-4), 7.42 (H-6) and carbon signal δC148.5(C-2)、167.7(C-10)
Correlation, fragrant Hydrogen Proton signal δH6.57 (H-5'), 6.47 (H-6') respectively with carbon signal δC147.0
(C-3'), 144.3 (C-4') is related, confirms foundation on phenyl ring further1H,13C-NMR and HSQC
The hydrocarbon ownership that spectrum speculates.
Comprehensive information above it is determined that the planar structure of compound A, pass through by the absolute configuration of this compound
Optically-active and CD determine.Because there is 1 chiral centre in structure, compare document (Allen, A.E.；
MacMillan, D.W.C.J.Am.Chem.Soc.2011,133,4260) in similar structures
Optical data, determines that the absolute configuration of 7 carbon in compound is R.Through Scifinder database retrieval,
For a noval chemical compound having no document report, it is named as (R) -1,2- driffractive ring Ceplignan.
Table 1. compound A's1H NMR(600MHz,DMSO-d6),13C NMR(150MHz,DMSO-d6) spectrum
Data
Table 2. compound B's and C1H NMR(400MHz,CD3OD),13C NMR(150MHz,CD3OD) compose
Data
Above-mentioned (2S, 3R)-Ceplignan (B, Fig. 1) and (2R, 3S)-Ceplignan (C, Fig. 1) are
A pair of optical isomer, CD composes as shown in fig. 6, determining this two changes with reference to table 2, Fig. 4 and Fig. 5
The chemical constitution of compound and absolute configuration.
Embodiment 2
The impact to 5-hydroxy tryptamine transporter (SERT) for the phenylpropanoids of the present invention
Using the hSERT-HEK293 cell strain of stable transfection, with 4- (4- (dimethylamino) phenyl)
-1-methylpyridinium(APP+) it is fluorogenic substrate, Phenylpropanoid Glycosides class is detected on high intension system
The impact to SERT activity for the compound.
1) experimental apparatus and reagent
Experimental apparatus：
High intension Operetta system and Columbus data management and analysis system (PerkinElmer),
Super-clean bench, liquid-transfering gun (1000 μ L, 200 μ L, 20 μ L, 10 μ L, 2.5 μ L, U.S. Eppendorf
Company)
Reagent and material：
Human embryonic kidney cell line HEK293 (American Type Culture Collection committee of Chinese Academy of Sciences cell bank), hSERT
PcDNA3 plasmid (Addgene, plasmid 15483), MEM culture medium (Gibco), APP+ (Sigma),
Hoechst 33342 (Cell Signaling Technology), 96 orifice plates (Costar 3605)
2) experimental implementation process
{ peace is of heap of stone, Li Jing, golden blast to initially set up and identify stable expression hSERT-HEK293 cell strain
Deng. the foundation of people source 5-hydroxy tryptamine transporter stable expression cell line and its function investigation [J]. military doctor
Learn 2011,35 (9):681-684}.With APP+For fluorogenic substrate, based on high intension system detectio SERT
Function { Fowler A, Seifert N, Acker V.et al.A nonradioactive
high-throughput/high-content assay for measurement of the human
serotonin reuptake transporter function in vitro[J].Journal of
Biomolecular Screening,2006,11(8):1027-1034}.
Concrete steps：
(1) precision weighs phenylpropanoids, is configured to the mother solution of 20mM with DMSO, with no phenol
Training base dilution medicine in red MEM basis is to 10M, 1.0M, 0.1M.
(2) 1.0 × 10 are pressed4The density of cells/well inoculates the hSERT-HEK293 cell of stable transfection to 96
In orifice plate, at 37 DEG C, 5%CO2Under the conditions of cultivate 24h.
(3) blank control group, positive control 2M Fluoxetine group and 1M are set up in experiment
Tianeptine, phenylpropanoids 10M, 1.0M, 0.1M group.Cell discards culture
Base, is washed 2 times with PBS, adds each testing sample, each concentration 3 according to 80L/ pore volume
Individual multiple holes, at 37 DEG C, 5%CO2Under the conditions of lucifuge incubation 2-3h.
(4), after the completion of being incubated, every hole adds 20L APP+, it is incubated 10 minutes.
(5) discard the liquid of in the hole, washed 2 times with PBS, every hole adds 1.0g/mL
Hoechst 50L, lucifuge is incubated 20min.
(6) discard the liquid in orifice plate, PBS washes 2-3 time, intracellular using high intension system detectio
Fluorescence intensity：
Hoechst 33342 Excitation：360-400nm, Emission：410-480nm
APP+Excitation：460-490nm, Emission：505-550nm.
3) data analysiss：
Graphical analyses are carried out using Columbus data management and analysis system, according to Hoechst 33342
Fluorescence identifying nuclear pattern determining cell, according to intracellular APP+Fluorescence intensity come to determine SERT transhipment live
Property, calculate relative intensity of fluorescence=(intracellular APP+Fluorescence intensity medicine group/intracellular APP+Fluorescence intensity compares
Group) carry out ANOVA analysis.
4) experimental result
Experimental result is as shown in Fig. 2 result display compound A significantly inhibits SERT transport activity (F (5,65)
=269.4, p<0.0001), Dunnett's multiple comparison post hoc test card
Real 10.0M (q=6.697, p<0.001), 1.0M (q=0.1903, n.s.), 0.1M
(q=0.3888, n.s.), positive controls 2.0M Fluoxetine is compared with blank control group
Significantly suppress SERT activity (q=30.16, p<0.001), positive controls Tianeptine are at 1.0 μM
When can significantly increase SERT activity (q=5.340, p<0.001).
Result display compound B significantly increase SERT transport activity (F (5,61)=378.3,
p<0.0001), Dunnett's multiple comparison post hoc test confirms 10.0M
(q=4.608, p<0.001), 1.0M (q=0.5391, n.s.), 0.1M (q=2.104,
), n.s. positive controls 2.0M Fluoxetine significantly suppress SERT compared with blank control group
Active (q=34.22, p<0.001), positive controls Tianeptine can significantly increase when 1.0 μM
Strong SERT activity (q=6.060, p<0.001).
Result display compound C significantly increase SERT transport activity (F (5,68)=389.6,
p<0.0001), Dunnett's multiple comparison post hoc test confirms 10.0M
(q=3.377, p<0.01), 1.0M (q=1.759, n.s.), 0.1M (q=1.048,
), n.s. positive controls 2.0M Fluoxetine significantly suppress SERT compared with blank control group
Active (q=35.01, p<0.001), positive controls Tianeptine can significantly increase when 1.0 μM
Strong SERT activity (q=6.199, p<0.001).
In summary, described 5-hydroxy tryptamine transporter (SERT) is that a kind of have high affinity to 5-HT
Transmembrane transporter, placenta tissue, bone marrow, kidney, lung, the heart, adrenal gland, liver, parathyroid gland,
The organs such as thyroid, pancreas and small intestinal are all distributed, and belong to Na+/Cl-Dependent form transport protein, main position
In 5-HT serotonergic neuron, reuptake 5-HT from nerve synapse gap and enter presynaptic neuron, directly
Connect impact synaptic space 5-HT concentration, change amount and the acting duration that postsynaptic receptor mediates signal,
Thus participating in multiple Physiological Psychology functions (as emotion, appetite, sleep, memory, study etc.).
SERT inhibitor is clinical treatment depression, anxiety neurosis, obsession, phobia, schizophrenia
The mental illness such as disease, and the slow gastrointestinal work(such as Constipation, irritable bowel syndrome, functional distension
A kind of medicine of energy property disease.Fluoxetine, paroxetine, Sertraline, fluvoxamine, citalopram etc.
Clinical common medicine, all belongs to such.Such medicine sedation is little, does not also damage Psychomotor ability, right
Cardiovascular and autonomic nervous system function impact very little.
The phenylpropanoids that the present invention passes through separation from Rhizoma Acori Graminei rhizome is obtained are adjusted in vitro
The research of 5-hydroxy tryptamine transporter (SERT) activity, finds that phenylpropanoids can remarkably promote SERT
Transport activity, thus confirming phenylpropanoids is the unbalance relevant physiological psychology disease causing of suppression SERT
Disease one of effective ingredient.Therefore, phenylpropanoids can be used to the lifes such as preparation treatment depression
The medicine of reason mental illness.
Embodiment 3
Preparation method：According to the above ratio phenylpropanoids, newborn sugar and starch are uniformly mixed, cross 200
Mesh sieve, uses water uniform wet, the mixture drying after moistening after sieve, adds magnesium stearate, then
By mixture tabletting, every weight 250mg, active component content is 10mg.
Embodiment 4
Capsule：Phenylpropanoids 20mg
Galactose 188mg
Magnesium stearate 2mg
Preparation method：According to the above ratio phenylpropanoids are uniformly mixed with galactose, cross 200 mesh
Sieve, the mixture obtaining, adds magnesium stearate, loads No. 2 capsules, obtain final product.
Above-mentioned with reference to specific embodiment, this phenylpropanoids and preparation method and application are carried out
Describe in detail, be illustrative rather than determinate, can be included several according to limited scope real
Apply example, therefore changing and modifications under without departing from present general inventive concept, the protection model of the present invention should be belonged to
Within enclosing.
Claims (5)
1. phenylpropanoids, have following structural formula (B), (C) formula：
Wherein, B is (2S, 3R)-Ceplignan, and C is (2R, 3S)-Ceplignan.
2. phenylpropanoids described in claim 1 preparation method it is characterised in that：Concrete steps
As follows：
(1) every 20kg Rhizoma Acori Graminei rhizome is boiled 3 times with the decocting of 8,6,6 times of weight respectively, and 1.5 is little every time
When, united extraction liquid, it is evaporated to the 1/5-1/10 of extracting liquid volume, obtain crude extract concentrated solution；
(2) gained crude extract concentrated solution, through D101 macroporous resin column chromatography, alcohol-water (v/v) gradient
Eluting, obtains 30%, 50%, 70%, 95%4 ethanol elution things, decompression and solvent recovery is to no alcohol respectively
Taste；
(3) adjust pH=3-4 with formic acid after 30% ethanol elution thing moisture being dissipated, equal-volume n-butyl alcohol extracts
Take 3 times, recycling design obtains n-butanol layer extractum；
(4) n-butanol layer extractum, through ODS column chromatography, methanol-water (v/v) gradient elution, collects 20% first
Alcohol water elution stream part, gained flow point separates through Sephadex LH-20 gel column 50% methanol-water (v/v)
5 components, wherein component SDB2-4 separate through semipreparative high performance liquid chromatography and obtain (2S, 3R)-cattle
Lignin and (2R, 3S)-Ceplignan.
3. phenylpropanoids described in claim 1 adjust 5-hydroxy tryptamine transporter active medicine in preparation
The application of aspect.
4. phenylpropanoids described in claim 1 are preparing depression, anxiety neurosis, schizophrenia
Disease, obsession, the treatment of neurodegenerative diseases, drug addiction or digestive system function disorders
The application of medicine aspect.
5. there is the pharmaceutical composition of phenylpropanoids described in claim 1 it is characterised in that：Bag
Phenylpropanoids containing treatment and/or prevention effective dose and optional pharmaceutically acceptable excipient.
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| AKIYO SAKUSHIMA 等: "Dihydrobenzofuran lignans from Boreava orientalis", 《PHYTOCHEMISTRY》 * |
| SHUANG LIANG 等: "A novel sesquiterpene and three new phenolic compounds from the rhizomes of Acorus tatarinowii Schott", 《BIOORG. MED. CHEM. LETT.》 * |
| 于洋 等: "栀子中的木脂素类成分研究", 《中草药》 * |
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