CN104997786A - Application of bemesedin as TRPA1 channel agonist in preparation of medicines - Google Patents
Application of bemesedin as TRPA1 channel agonist in preparation of medicines Download PDFInfo
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- CN104997786A CN104997786A CN201510411304.1A CN201510411304A CN104997786A CN 104997786 A CN104997786 A CN 104997786A CN 201510411304 A CN201510411304 A CN 201510411304A CN 104997786 A CN104997786 A CN 104997786A
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- China
- Prior art keywords
- trpa1
- bimatoprost
- application
- channel agonist
- bemesedin
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Abstract
The invention discloses an application of bevacizumab as a TRPA1 channel agonist in preparation of a medicament. Use of bevacizumab as a TRPA1 channel agonist in the manufacture of a medicament, the bevacizumab exerting a therapeutic effect by acting on TRPA1 for the treatment of hearing disorders, for modulating gastrointestinal motility and for oxytocic. The application of the bemesedin as a TRPA1 channel agonist in preparing an intraocular pressure reducing medicine, and the bemesedin takes TRPA1 as a target point to play an intraocular pressure reducing role so as to effectively treat related diseases. Bemesedin can enhance the mechanosensitivity of mechanosensitive trigeminal nerve endings by activating the TRPA1 channel. The eye pressure change information is more sensitive, so that stronger feedback regulation is promoted to reduce the eye pressure.
Description
Technical field
The present invention relates to drug world, refer to that Bimatoprost is preparing the application in medicine as TRPA1 channel agonist particularly.
Background technology
Bimatoprost (17-Phenyl-tri-norprostaglandin F
2 α-ethyl amide, bimatoprost) molecular formula: C
25h
37nO
4, molecular weight: 415.57, molecular structure:
Bimatoprost is prostatitis amide F (2 α) derivant of synthesis, flowed out by the aqueous humor increasing meshwork of angle of anterior chamber passage and uveal scleral passage and reduce intraocular pressure (IOP), being considered to the local anti-glaucoma medicine that current reducing iop is the strongest.Bimatoprost is mainly used in the patient of open angle glaucoma (POAG) or ocular hypertension (OHT), and systemic adverse reactions is less.Research shows that Bimatoprost can not activate FP receptor and can not activate EP receptor, and its intraocular pressure lowering mechanism may differ from other prostaglandins intraocular pressure lowering medicines.Up to now, there is not been reported for the action passage that Bimatoprost is definite.
The gene of TRPA1 is clone from lung fibroblast for 1999 at first, and it is named as ANKTM1 at first, comprises the aminoterminal many ankyrin repeats of N-.Mankind TRPA1 gene comprise 27 exons and at 8q13 chromosome across 55701 bases.TRPA1 gene code one about 1,100 amino acid protein molecules, about 120-130kDa, TRPA1 may form a functive by the homotetramer of TRPA1 albumen, TRPA1 topological structure is similar to other TRP albumen, be made up of 6 transmembrane segments (S1-6), between the penetrating zone location S5-S6 of ion, first outer loop ring of born of the same parents comprises 2 aspartic acid glycosylated region between S1-S2.N-end comprises nearly 18 ankyrin repeats be made up of 33 aminoacid, and it may be protein-protein interaction, as the reciprocal action of passage and plasma membrane.The ARDs region of TRPA1 is deleted rear display channel insertion plasma membrane and is affected.In the district of 17 ankyrin repeats, when calcium ion is connected to ARD district, change the structure of whole N-end, add its hardness, decrease space length.In the trans-membrane region of TRPA1, N855 is the important remnants near TM5 region, relevant with familial dispersibility pain syndrome, between S4-S5, form a firm chain be attached to helical region and S1, therefore between N-end and passway, form a direct power transmission chain.The importance in EF hand-type region need research, because the point mutation in this region only affect the mechanism that calcium ion relies on activity in right amount, but lacks or deletes and but make the reciprocal action of passage and plasma membrane weaken.The acid that other possible calcium ion chelating regions remain in TRPA1C-end by a group forms, mankind TRPA1 has 4 conservative regions, Glu1077, Asp1080, Asp1081and Asp1082, to calcium ion rely on and voltage independent voltage and or agonist induction reaction inactivation have important relationship, the amino acid whose C-end of selective retention 20 blocks, the inactivation that the calcium ion that slowed down relies on, does not affect other functional parameters.Show the nucleic acid group of the Homoeology of the calcium connecting portion of leading potassium channel with large calcium, a kind of calcium ion sensitizing range of long-term searching may be represented.They have determined that the multiformity of TRPA1 drug target.
TRPA1 wide expression is on dorsal root ganglion (DRG), trigeminal ganglion (TG), meckel's ganglion (NG) these sensory nerves, and the corti device (relevant with audition) of internal ear.Along with going deep into of people's understanding, find TRPA1 also wide expression in the non-neuronal cells of many tissues and organ, comprise skin, heart, gastrointestinal, lung, skeletal muscle, pancreas and vaginal cell, participated in various function, to regulate in body surely.
TRPA1 is a kind of mechanosensitive ion channels (MS passage) discussed warmly, can directly be activated by mechanical stimulus or indirect regulation mechanical signal intensity; Existing a lot of experimental evidence supports the mechanoreception conduction of TRPA1.The TRPA1 being distributed in dermal sensation centripetal fiber end can react to harmful chemicals and mechanical stimulus.TRPA1 gene mutation can cause nose to contact the mechanical sensitivity such as response behavioral deficiency.TRPA1 great expression is in DRGs, and the mechanical force of local stimulates DRG neuron can bring out mechanical sensitivity electric current fast.TRPA1 is relevant with gastrointestinal inflammatory pain, neuron innervation gastrointestinal tract 3 zoness of different of nodosum ganglion and DRGs, allly all expresses TRPA1, has the function increasing mechanical sensitivity and adjustment internal organs nociception at normal and inflammatory tissue.Also studies have found that the agonist of TRPA1 can the mechanical sensitivity of enhanced sensitivity bladder.Research finds that the genome of Brachydanio rerio has two TRPA genes, is TRPA1a and TRPA1b respectively, finds after processing Brachydanio rerio with morpholino (can reduce the expression of TRPA1a in zebrafish embryo), and inner ear hair cells conductive electric current reduces.Disturb the expression of Brachydanio rerio TRPA1 also can reduce the conductive electric current of hair cell with RNAi (RNA interference).These evidences show that TRPA1 may play a role as auditory sensor.
Cyclopentenone prostanoid (Cyclopentenone prostaglandins, PGs): 15-d-PGJ2, PGA2 and PGA1, have highly active α, beta-unsaturated carbonyl, directly can activate TRPA1; Cinnamic aldehyde (Cortex Cinnamomi), isothiocyanate [mustard oil (Mustard oil, MO or Allyl isothiocyanate, AITC), Radix Cochleariae officinalis] and allicin (allicin) and delta 9 tetrahydrocannabinol (Δ (9) – tetrahydracannabinol, Δ 9THC, Fructus Cannabis) be the agonist of TRPA1; Intravenous anesthetic propofol (Propofol) can activate TRPA1; Methyl parahydroxybenzoate (Methyl paraben) adds medicine, cosmetics and food to usually used as antibacterial, is also the non-electrophilic agonist of TRPA1 passage.The Fructus Perillae reactive compound perillaldehyde of Labiatae family and perilla ketone are all the agonist of TRPA1, and Folium Perillae cotyledon is usually used in the handicapped Chinese medicine for the treatment of stomach.Eugenol is a kind of benzene alkene, for spice, flavouring agent, medically can be used as antiseptic and local anesthetic.The similar pungent compound gingerol also had in Rhizoma Zingiberis Recens (fresh ginger), eugenol and gingerol can activate TRPA1 passage effectively.In the agonist of TRPA1, PGA2 and propofol have been proved and have had reducing iop.
Summary of the invention
The invention provides a kind of Bimatoprost and prepare the application in medicine as TRPA1 channel agonist.
To achieve these goals, the invention provides a kind of Bimatoprost and prepare the application in medicine as TRPA1 channel agonist, Bimatoprost plays therapeutical effect by acting on TRPA1, being used for the treatment of dysaudia, regulating gastrointestinal tract dynamia and for hastening parturition
The invention provides a kind of Bimatoprost and preparing the application in intraocular pressure lowering medicine as TRPA1 channel agonist, Bimatoprost plays reducing iop using TRPA1 as target spot.
Present invention also offers a kind of Bimatoprost by effective dose and pharmaceutically acceptable accessory drugs forms medicine.
Further, described pharmaceutically acceptable accessory drugs is vitamin C, sorbitol, mannitol, fructose, aminoacid, glucosan, dextrin or sucrose.
Beneficial effect of the present invention is:
The invention provides the U.S. prostate of shellfish is a kind of new TRPA1 agonist, can be used for the preparation of medicines such as treating dysaudia, adjustment gastrointestinal tract dynamia and hasten parturition, effectively can treat relevant disease.
The invention provides a kind of TRPA1 is the critical medication target spot that Bimatoprost plays reducing iop, thus treatment ocular disease.Bimatoprost by activating TRPA1 passage, can strengthen the mechanical sensitivity of mechanical sensitivity nervi trigeminus tip.Make it more responsive to intraocular pressure transition information, thus inspire stronger feedback regulation reduction intraocular pressure.
Accompanying drawing explanation
Fig. 1 is the expression figure of TRPA1 in domination rat camera oculi anterior inwall nervi trigeminus unit;
Fig. 2 is that Bimatoprost activation TRPA1 causes nervi trigeminus unit flow of calcium ions figure;
Fig. 3 is the flow of calcium ions figure that Bimatoprost causes hTRPA1HEK 293 cell;
Fig. 4 is the flow of calcium ions figure that the Bimatoprost of Concentraton gradient causes nervi trigeminus unit;
Fig. 5 is the TRPA1 map of current that Bimatoprost excites domination rat camera oculi anterior inwall nervi trigeminus unit;
Fig. 6 is the mechanosensitive ion channels figure that TRPA1 participates in composition domination rat camera oculi anterior inwall nervi trigeminus unit;
Fig. 7 is the mechanical sensitivity figure that Bimatoprost activates TRPA1 enhanced sensitivity domination rat camera oculi anterior inwall nervi trigeminus unit.
Detailed description of the invention
In order to explain the present invention better, illustrate main contents of the present invention further below in conjunction with specific embodiment, but content of the present invention is not only confined to following examples.
Embodiment 1
1, Dil neuron retrograde labeled
Receptor or passage are present in pericaryon and tip simultaneously, and therefore usual cell space replaces too small tip to study, and the conclusion that cell space draws is equally applicable to tip.We study to replace teleneuron with the nervi trigeminus unit cell space of Dil camera oculi anterior injection labelling domination rat camera oculi anterior interior wall construction.3-5 μ l fluorescent tracer Dil (2.5mg/ml) is injected in rat camera oculi anterior through cornea by glass microelectrode.After having injected, rat prohibits water one day, normally takes food.
2, trigeminal ganglion immunofluorescence dyeing
Dil to inject after anterior chamber the 3rd day, after chloral hydrate (4ml/kg) the intraperitoneal injection of anesthesia rat of 10%, fixes through left ventricle perfusion with 4% paraformaldehyde.Broken end decerebrate, takes out trigeminal ganglion, fixes 4-6h after putting 4% paraformaldehyde 4 DEG C, then puts 30% sucrose 4 DEG C dehydration to sinking to the bottom, by freezing microtome coronalplane serial section, and thickness 30 μm.After rinsing is changed thoroughly, add 1:100 anti-TRPA1 antibody/1% sheep blood serum, 4 DEG C of overnight incubation.After rinsing, add goat anti-rabbit igg antibody/1% sheep blood serum of 1:50FITC labelling, under being placed in room temperature condition, hatch 3h.30% glycerol mounting, observes imaging after mounting dries under Laser Scanning Confocal Microscope.
3, TRPA1 is in the expression of domination rat camera oculi anterior inwall nervi trigeminus unit
Application immunofluorescence location technology altogether, TRPA1 albumen (green fluorescence) is extensive strongly expressed on nervi trigeminus unit after birth, strongly expressed on all nervi trigeminus cell membranes of Dil labelling (redness).(see Fig. 1)
4, cell is drawn materials
Dil to inject after anterior chamber the 3rd day, and chloral hydrate (4ml/kg) the intraperitoneal injection of anesthesia rat of 10%, broken end decerebrate, take out trigeminal ganglion, sharp separation goes out nervi trigeminus unit.Digestive system by the Hanks balanced salt solution of 2ml, the papain of 75 μ l, the collagenase of 75 μ l and 75 μ l-cysteine mixes, Tris-OH regulates PH to neutral or slightly meta-alkalescence is formulated.On the coverslip of the cell seeding that separation obtains in culture dish.Leave standstill within 30 minutes, treat cell attachment, add in culture dish subsequently DMEM-F12,10% hyclone, 100Units/mL dual anti-(penicillin/streptomycin).Be positioned over subsequently and hatched 3-12h 37 DEG C contain in the CO2 incubator of the O2 and 5% of 20%, afterwards for patch clamp experiments and the experiment of calcium image.
5, calcium image
Inoculation nervi trigeminus unit on the cover slip or HEK293 cell are added the extracellular fluid of the Fura-2AM containing 1 μm of ol/L, is placed in that the incubator of 37 DEG C is opacus hatches 40min.Cell after load is put into the moveable cell groove of inverted microscope, by excitation source, (wavelength is 340nm and 380nm, interval time 1s), Fura-2 is excited, through CCD imaging system and Tillvision software collection and analysis, namely obtain the fluorescence ratio of Ratio=F340/F380, this Ratio value reflects cell [Ca2+] i indirectly, and utilizes Sigmaplot8.0 to analyze further.
Extracellular fluid component (mM): NaCl 140, KCl 5, MgCl2.6H2O 1, CaCl22, D-Glucose 10, HEPES 10mM, Tris-OH regulates PH=7.4..
Statistical analysis: baseline calcium concentration value ([Ca2+] b)=the average calcium ion concentration of the Baseline detection of 2min, Ratio (340/380nm) value=[Ca2+] x/ [Ca2+] b of each time point.Response strength Δ Ratio=(b)/[Ca2+] b of the average Ratio-[Ca2+] after administration within 2min.The cell of Δ Ratio>2S.D just includes statistics in, and continuous data is with mean ± standard error (Mean ± S.E.M), and R-3.0.2 analyzes, and adopts rank test.
6, Bimatoprost activation TRPA1 causes nervi trigeminus unit flow of calcium ions
The cell calcium image experiment of application rat trigeminal unit, by the matched group only giving extracellular fluid in advance and hatch, give TRPA1 specific inhibition agent HC-030031 (25 μMs) or TRP family specificity blocker RR (30 μMs) in advance to hatch and be divided into 3 groups, all give the Bimatoprost effect 120s of 25ng/mL in extracellular after, obtain different intracellular calcium changes.Latter two groups have significant significant difference (P with Bimatoprost group
vehicle-Bimatoprost vs hC-Bimatoprost<0.01, P
vehicle-Bimatoprost vs rR-Bimatoprost<0.01).AITC group is as positive control.(see Fig. 2)
7, HEK293 cell culture
The HEK293 cell (hTRPA1HEK293cells) of the stably express hTRPA1 purchased and the HEK293 cell (nt-TRPA1HEK293cells) of not expressing hTRPA1 are cultivated, is ready to use in patch clamp experiments and the experiment of calcium image.On the coverslip of hTRPA1HEK293 and nt-TRPA1 HEK293 cell seeding in culture dish, use the DMEM culture medium containing 10%FBS (containing 1.5mM L-Glutamine, 100U/ml Penicillin, 100 μ g/ml Streptomycin) cellar culture, 37 DEG C, 5%CO
2cultivate in saturated humidity incubator, treat that it is well adherent, incubation time is less than 48 hours.
8, Bimatoprost causes the flow of calcium ions of hTRPA1HEK 293 cell
In hTRPA1HEK293 extracellular application Bimatoprost (25ng/mL), induce the growth of the various patterns of intracellular calcium concentration; After eluting Bimatoprost, after cytotostatic, above-mentioned extracellular application TRPA1 specific agonist AITC (100 μMs), the various growths inducing intracellular calcium equally become.But there is no similar change, (see Fig. 3) in HEK293 cell (nt-TRPA1HEK293cells) group (nt-TRPA1-HEK) not expressing hTRPA1
9, the Bimatoprost of variable concentrations gradient causes the flow of calcium ions of nervi trigeminus unit
We carry out calcium image and the research of Bimatoprost Concentraton gradient on the trigeminal ganglion neuron of acute isolation.The growth of the Bimatoprost induction intracellular calcium in various degree of 5ng/mL, 25ng/mL, 50ng/mL, 100ng/mL, 200ng/mL concentration is added respectively in extracellular.The statistical testing results is followed successively by: P
5vs control<0.01; P
25vs control<0.01; P
50vs control=0.010; P
100vs control<0.05; P
200vs control>0.05.When giving the Bimatoprost of 25ng/mL concentration, obtain maximum calcium ion amplification.(see Fig. 4)
10, Whole-cell recording
HEKA EPC-10 patch clamp amplifier is connected on computer and then in nervi trigeminus unit by D/A and A/D converter and implements whole-cell patch-clamp experiment.Select the whole-cell recording technique that after birth is smooth, refractivity good, third dimension is strong round cell carries out patch-clamp.Electrode enters water resistance and resists for 2-4M Ω, interpolation filamentary silver is connected with patch clamp amplifier, compensate liquid junction potential, electrode moves to directly over cell, light pressure cell Light deformation, after regulating micro-behaviour to make electrode and cell form high resistance seals under inverted fluorescence microscope, compensate fast electric capacity C-Fast, pulsating negative pressure suction rupture of membranes, slow electric capacity C-Slow compensates, Selection parameter record, sealing-in resistance is compensated during experiment, and then reduce electric capacity to the impact of the channel current be recorded to, in whole experiment, high impedance sealing-in > 1GB, the inward electric current that voltage-clamp mode record medicine irritation produces, Clamping voltages is-60mV.
Extracellular fluid component (mM): NaCl 140, KCl 5, MgCl
2.6H
2o 1, CaCl
22, D-Glucose 10, HEPES 10mM, Tris-OH regulate PH=7.4, the composition (mM) of liquid in electrode: K-Asp 118, KCl 20, MgCl
2.6H
2o 2, CaCl
21, EGTA 10, HEPES, 10, Na
2aTP 5mM, Tris-OH regulate PH=7.2,
The mensuration of current intensity: the difference between electric current amplitude peak has just appearred in electric current in activation process.The mensuration of electric current density: experimental record software directly draws membrane capacitance, electric current density is the ratio (PA/PF) of current intensity and membrane capacitance, and continuous data represents with mean ± standard deviation (Mean ± S.E.M), and R-3.0.2 analyzes.Adopt rank test.P < 0.05 thinks to have statistical significant difference.
11, Bimatoprost excites the TRPA1 electric current of domination rat camera oculi anterior inwall nervi trigeminus unit
At Clamping voltages (Holding Potential, HP) during-60mv, when giving the nervi trigeminus unit cell space that Bimatoprost (25ng/mL) acts on Dil labelling, be recorded to inward electric current, its average current density is 29.11 ± 11.83.After Bimatoprost eluting, give after HC-030031 (25 μMs) hatches 3min, extracellular gives Bimatoprost (25ng/mL) again, and the current amplitude be recorded to is comparatively front obviously to be lowered, and average current density is 8.52 ± 4.00.HC-030031 contrasts before and after hatching has remarkable significant difference.(see Fig. 5)
12, the applying of mechanical stimulus
Extracellular fluid spurt method is adopted to apply mechanical stimulus to neuron, on electrode anchors, be connected with a glass-micropipe (tip diameter is about 2-3 μm) by micro-behaviour, glass-micropipe draws instrument two-step method through electrode and draws, glass-micropipe is connected with automatic tire pump, Patch Control 4 (Nanion technologies, GmbH, Germany) software control pulsometer produces the injection air pressure that 0mmHg to 50mmHg does not wait.
13, TRPA1 participates in the mechanosensitive ion channels of composition domination rat camera oculi anterior inwall nervi trigeminus unit
We are on the cell of Dil labelling, application whole-cell patch-clamp, when Clamping voltages-60mv, application 30mmHg sprays pressure and sprays extracellular fluid to nervi trigeminus unit cell space, be recorded to inward electric current, on same neuron, give after HC-030031 (25 μMs) hatches 3min, again apply the mechanical stimulus of equality strength, the inward electric current intensity losses be recorded to, add before HC-030031 hatches, the average current density of the mechanical sensitivity electric current be recorded to is 39.19 ± 14.39, the average current density of the mechanical sensitivity electric current be recorded to after hatching is 20.65 ± 6.28, dosing forward backward averaging electric current density relatively there is significant difference.(see Fig. 6)
14, Bimatoprost activates the mechanical sensitivity of TRPA1 enhanced sensitivity domination rat camera oculi anterior inwall nervi trigeminus unit
We apply whole-cell patch-clamp, and when Clamping voltages-60mv, application 30mmHg sprays pressure and sprays extracellular fluid, act on the nervi trigeminus unit cell space of Dil labelling, are recorded to inward electric current.On same neuron, give after Bimatoprost (25ng/mL) hatches 3min, again apply the mechanical stimulus of equality strength, the inward electric current intensity enhancing be recorded to, by medicament elution, treat cytotostatic, give after HC-030031 (25 μMs) hatches 3min, again add Bimatoprost (25ng/mL) and hatch 3min, again give the mechanical stimulus of equality strength, the inward electric current intensity be recorded to is more previous to be weakened, by medicament elution, treat cytotostatic, then give the mechanical stimulus of equality strength, current intensity is recovered.(see Fig. 7)
Known by above-mentioned experiment; Bimatoprost by activating TRPA1 passage, can strengthen the mechanical sensitivity of mechanical sensitivity nervi trigeminus tip.Make it more responsive to intraocular pressure transition information, thus inspire stronger feedback regulation reduction intraocular pressure.Some researchs carried out on Visceral sensory neurons also point out the activation of TRPA1 to have the effect of enhanced sensitivity mechanical sensitivity teleneuron.
Other unspecified part is prior art.Although above-described embodiment is to invention has been detailed description; but it is only the present invention's part embodiment; instead of whole embodiment, people can also obtain other embodiments according to the present embodiment under without creative prerequisite, and these embodiments all belong to scope.
Claims (4)
1. Bimatoprost is preparing the application in medicine as TRPA1 channel agonist, it is characterized in that: Bimatoprost plays therapeutical effect by acting on TRPA1, being used for the treatment of dysaudia, regulating gastrointestinal tract dynamia and for hastening parturition
2. Bimatoprost is preparing the application in intraocular pressure lowering medicine as TRPA1 channel agonist, it is characterized in that: Bimatoprost plays reducing iop using TRPA1 as target spot.
3. according to claim 1 or 2, medicine is made up of the Bimatoprost of effective dose and pharmaceutically acceptable accessory drugs.
4. Bimatoprost is preparing the application in medicine as TRPA1 channel agonist according to claim 3, it is characterized in that: described pharmaceutically acceptable accessory drugs is vitamin C, sorbitol, mannitol, fructose, aminoacid, glucosan, dextrin or sucrose.
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|---|---|---|---|---|
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Non-Patent Citations (1)
| Title |
|---|
| 陈光胜等: "拉坦前列素、曲伏前列素及贝美前列素滴眼液治疗原发性开角型青光眼降眼压效果比较", 《中国老年学杂志》 * |
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| CN113545316B (en) * | 2020-04-24 | 2022-05-17 | 中国科学院上海药物研究所 | Application of sanguinarine in preparation of TRPA1 channel agonist |
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Application publication date: 20151028 |
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| RJ01 | Rejection of invention patent application after publication |