CN114732819A - Application of Yoda1 as active ingredient in preparation of airway smooth muscle relaxant - Google Patents
Application of Yoda1 as active ingredient in preparation of airway smooth muscle relaxant Download PDFInfo
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- CN114732819A CN114732819A CN202210398685.4A CN202210398685A CN114732819A CN 114732819 A CN114732819 A CN 114732819A CN 202210398685 A CN202210398685 A CN 202210398685A CN 114732819 A CN114732819 A CN 114732819A
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- smooth muscle
- airway smooth
- yoda1
- relaxing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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Abstract
The invention discloses application of Yoda1 as an active ingredient in preparation of an airway smooth muscle relaxation agent, and experiments show that the compound shown in the formula I can activate Piezo1 and strongly relax airway smooth muscle cells, and the relaxation degree of the compound is close to that of isoproterenol and salbutamol. The compound shown in the formula I can be used for preparing a medicine for relaxing airway smooth muscle, and can also be used for preparing an airway smooth muscle relaxing agent, so that the compound is used for treating asthma, chronic obstructive pulmonary diseases and the like, and has wide application prospect.
Description
Technical Field
The invention belongs to the technical field of drug research and development, and particularly relates to application of Yoda1 as an active ingredient in preparation of an airway smooth muscle relaxant.
Background
Asthma is a chronic respiratory disease with up to 3.39 million people suffering from asthma worldwide. Asthma is typically characterized by airway hyperresponsiveness, which is manifested by faster and stronger contraction of airway smooth muscle cells by stimuli. Airway smooth muscle cells exist in the middle and periphery of the airway wall, spirally surrounding the airway, and thus contraction of airway smooth muscle cells leads to airway constriction and obstruction. The current research direction for asthma drug development is mainly focused on how to relax asthma airway smooth muscle cells.
According to the global asthma control protocol (2020 edition), one of the therapeutic drugs for asthma is bronchodilators, i.e. agents that relieve airway obstruction by relaxing airway smooth muscle cells. Suction type beta2Receptor agonists, the most effective bronchodilators currently on the market, provide relief from dyspnea and other symptoms, but have poor control over symptoms in severe asthma patients. Although severe asthma patients account for 5-10% of all asthma patients, severe asthma patients need more expensive drugs, are more likely to be hospitalized or need additional medical care, so the treatment cost of severe asthma patients accounts for more than half of the health care expenditure of asthma, and great economic burden is brought to asthma patients and society. Of particular importance is the long-term inhalation of beta2Receptor agonists cause a series of side effects such as drug tolerance. Therefore, the search for new airway smooth muscle cell relaxation drugs with novel action mechanisms is urgent.
Interestingly, the contraction of airway smooth muscle cells can be regulated not only by various chemical factors but also by mechanical factors. Indeed, the airways are indeed continuously exposed to mechanical environments, such as periodic stretching during tidal breathing or deep breathing in vivo. Studies have shown that periodic stretching reduces airway smooth muscle active contractility, so it has long been thought that deep-inspiration induced periodic stretching can mediate airway smooth muscle cell relaxation both in vivo and in vitro, but the mechanism of mechanical perception and signaling is unclear. In 2010, Piezo1 proved to be a novel mechanosensitive molecule whose mechanical activation could initiate a range of cellular responses, such as proliferation and migration, depending on the cell type and the associated microenvironment. Studies have shown that deep-aspiration induced cyclic stretching may relax airway smooth muscle cells by activating Piezo 1. However, the mechanical condition of external periodic tension is difficult to apply directly to the airway of asthma patients, and the corresponding chemical drugs may be more convenient for clinical application, so if the chemical activation of Piezo1 can also relax airway smooth muscle cells, the activators have important clinical significance, i.e. Piezo1 agonists may be potential drugs for treating airway diseases related to airway smooth muscle spasm such as asthma.
Although the chemical activation properties of Piezo1 have been discovered in 2015, two activators have been mainly discovered to date, including Euda 1(Yoda1) and Jeli. Compared with Jeli, the YOUDA 1 has lower concentration of onset of action and stronger activity, and is more suitable for clinical use. However, it has not been reported so far whether you da1 can relax airway smooth muscle cells by activating Piezo 1.
Disclosure of Invention
This section is for the purpose of summarizing some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. In this section, as well as in the abstract and the title of the invention of this application, simplifications or omissions may be made to avoid obscuring the purpose of the section, the abstract and the title, and such simplifications or omissions are not intended to limit the scope of the invention.
The present invention has been made keeping in mind the above problems and/or problems occurring in the prior art.
One of the objects of the present invention is to provide the use of Yoda1 as an active ingredient for the preparation of an airway smooth muscle relaxant.
In order to solve the technical problems, the invention provides the following technical scheme: the application of Yoda1 as an active ingredient in preparing an airway smooth muscle relaxant is disclosed, wherein the structure of Yoda1 is shown in formula I:
specifically, the compound with the structure shown in the formula I is Yoda1(CAS No.:448947-81-7), and the molecular formula is C13H8Cl2N4S2Molecular weight is 355.27g/mol, and it is insoluble in water. The International Union of Pure and Applied Chemistry (IUPAC) specifies the names: 2- ((2, 6-dichlobionyl) thio) -5- (pyrazin-2-yl) -1,3, 4-thiadiazole. The compound is named as: 2- ((2,6-dichlorobenzyl) thio) -5- (pyrazin-2-yl) -1,3, 4-thiadiazole; and more particularly to 1.
As a preferable scheme of the application of the invention, the Euda 1 relaxes airway smooth muscle cells by targeting a mechanosensitive ion channel Piezo 1.
The Piezo1 is a transmembrane mechanical sensitive ion channel, is widely distributed in animal bodies, and participates in functions of blood pressure regulation, touch perception and the like after mechanical activation.
The invention also aims to provide the application of the Eudaparinux 1 as an effective ingredient in preparing the medicine for relaxing the airway smooth muscle, wherein the structure of the Eudaparinux 1 is shown as the formula I.
As a preferable scheme of the application of the invention, the Euda 1 relaxes airway smooth muscle cells by targeting a mechanosensitive ion channel Piezo 1.
In a preferred embodiment of the use of the present invention, the airway smooth muscle relaxing drug is an asthma treatment drug.
By "treating" is meant reducing, inhibiting and/or reversing the development of asthma in a subject in need thereof. The term "treatment" includes any sign of successful treatment or improvement of asthma, including any objective or subjective parameter, such as remission; moderating; reduced symptoms or making the subject more tolerant to injury, pathology or condition; delay or slow the rate of development, etc. The measurement of treatment or improvement may be based on the results of physical examination, pathological examination, and/or diagnostic examination, for example, as known in the art.
Treatment may also refer to a reduction in the onset or outbreak of asthma, or a reduction in asthma recurrence (e.g., prolonging the time to recurrence) as compared to what would occur if the action were not taken.
The invention also aims to provide a pharmaceutical composition for relaxing airway smooth muscle, which at least comprises a compound shown in a structural formula I.
The invention also aims to provide a pharmaceutical preparation for relaxing airway smooth muscle, which contains a safe and effective amount of a compound shown as a structural formula I, and the balance of a pharmaceutically acceptable carrier.
As a preferable scheme of the pharmaceutical preparation for relaxing airway smooth muscle, the pharmaceutical preparation is an injection or a spray.
The term "pharmaceutically acceptable carrier" includes any or all of solvents, dispersion media, coatings, isotonic agents, absorption enhancers, absorption blockers, and the like that are physiologically compatible. Examples of the pharmaceutically acceptable carrier include saccharides such as water, saline solutions, Phosphate Buffered Saline (PBS), monosaccharides, disaccharides, oligosaccharides, polysaccharides (dextrin, dextran, isomaltose dextrin, cellulose, pullulan, chitin, chitosan, guar gum, carrageenan, and the like), derivatives thereof, alcohols such as glycerol, ethanol, and the like, and they may be used alone or in combination as appropriate. When used as an injection or the like, 1 or more kinds of pH adjusting agents, isotonic agents, sugar alcohols such as the above sugars, mannitol, sorbitol, maltitol, or sodium chloride may be used in combination as appropriate.
As a preferable scheme of the pharmaceutical preparation for relaxing airway smooth muscle, the pharmaceutical acceptable carrier in the injection solution is phosphate buffer solution or normal saline.
As a preferable mode of the pharmaceutical preparation for relaxing airway smooth muscle of the present invention, the pharmaceutical preparation for relaxing airway smooth muscle is a pharmaceutical preparation for treating asthma.
Compared with the prior art, the invention has the following beneficial effects:
the invention firstly reveals through experiments that the Eudara 1 can target and activate the mechanosensitive ion channel Piezo1 and can effectively relax airway smooth muscle cells, and the relaxation degree of the Eudara 1 is close to that of isoproterenol and salbutamol. The Eudara 1 is suggested to be used for preparing the medicine for relaxing the airway smooth muscle and the airway smooth muscle relaxing agent, thereby being used for treating asthma, chronic obstructive pulmonary diseases and the like and having wide application prospect.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without inventive exercise. Wherein:
FIG. 1 is a graph of the fitted dose-effect relationship of Ydar 1 in example 1 of the present invention;
FIG. 2 is a graph comparing the diastolic effect of Einda 1 and isoproterenol in example 1 of the present invention;
FIG. 3 is a graph showing the experimental results of the optical magnetic particle torsion cell analysis in example 2 of the present invention;
FIG. 4 is a graph showing the results of the airway diastolic function evaluation test of Euda 1 in example 3 of the present invention.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention more comprehensible, specific embodiments thereof are described in detail below with reference to examples of the specification.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
Furthermore, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
Unless otherwise indicated, the experimental methods, detection methods, and preparation methods disclosed herein are all conventional in the art. These techniques are well described in the literature and are described in detail in:
Kang Wen#,Kai Ni#,Jia Guo,Bing Bu,Lei Liu,Yan Pan,Jingjing Li,Mingzhi Luo*,and Linhong Deng*.MircroRNA let-7a-5p in airway smooth muscle cells is most responsive to high stretch in association with cell mechanics modulation.Frontiers in Physiology,2022,13,DOI:10.3389/fphys.2022.830406
Mingzhi Luo,Grace Cai,Kenneth.Ho,Kang Wen,Zhaowen Tong,Linhong Deng*,Allen P Liu*.Compression enhances invasive phenotype and matrix degradation of breast Cancer cells via Piezo1 activation.BMC Mol and Cell Biol,2022,23,1
Mingzhi Luo,Peili Yu,Kai Ni,Yang Jin,Lei Liu,Jingjing Li,Yan Pan,Linhong Deng*.Sanguinarine Rapidly Relaxes Rat Airway Smooth Muscle Cells Dependent on TAS2R Signaling.Biological&pharmaceutical bulletin,2020,43,1027-1034.
Mingzhi Luo,Kai Ni,Peili Yu,Yang Jin,Lei Liu,Jingjing Li,Yan,Pan,Linhong Deng*.Sanguinarine Decreases Cell Stiffness and Traction Force and Inhibits the Reactivity of Airway Smooth Muscle Cells in Culture.Molecular cellular biomechanics,2019,16,141-151.
Yue Wang,Yun Lu,Mingzhi Luo,Xiaohao Shi,Linhong Deng.Evaluation of pharmacological relaxation effect of the natural product naringin on in vitro cultured airway smooth muscle cells and in vivo ovalbumin-induced asthma Balb/c mice.Biomedical Reports,2016,5(6):715-722.
example 1
(1) Test object
Primary culture of human Airway Smooth Muscle Cells (ASMCs)
(2) Laboratory apparatus
Optical magnetic particle torsion cell analysis system (OMTC), living cell workstation, detachable 96-well plate, ultra-clean bench, CO2Cell culture box, low-speed centrifuge, cell counting plate, constant temperature water bath, autoclave, and confocal culture dish.
(3) Experimental procedure
Dose-dependent effects of ewda 1 (final concentration 0.01 μ M, 0.1 μ M, 1 μ M, 10 μ M, 100 μ M, 1000 μ M) were analyzed and compared with the effects of Isoproterenol (ISO) relaxation, a classical airway smooth muscle relaxation agent.
The specific method comprises inoculating cells into detachable 96-well plate at an inoculation density of 1 × 104And (3) changing an IT culture medium for culturing for 12 hours after the cells grow adherent to the ground for 24 hours, adding magnetic microbeads coated with the integrin antibody, and then dynamically detecting the change of the cell rigidity along with the treatment of different compounds by using an optical magnetic particle torsion cell measurement technique. The cell stiffness was measured for 1min in the basal state, followed by the addition of 10. mu.L of different concentrations, preferably up to 1, to measure the cell stiffness and thus reflect the degree of cell relaxation. The detection conditions are as follows: the frequency is 0.3Hz, and the detection time is 5 min.
(4) Results of the experiment
Experimental detection of Udada 1 dose-dependent Effect As a result, it was found that 5 concentrations of Udada 1 among the different tested concentrations showed significant diastolic effect (0.1. mu.M, 1. mu.M, 10. mu.M, 100. mu.M, 1000. mu.M), and EC was calculated by dose-effect curve fitting507.62 μ M. ASMCs were treated with Euda 1 at a concentration of 1 μ M, and it was found that cell rigidity decreased up to 32% after treatment of ASMCs with Euda 1 (see FIG. 1).
Further analysis and comparison of the relaxation effect of Euda 1 and isoproterenol revealed that the relaxation effect of Euda 1 was superior to that of isoproterenol after 50mM KCl was used to induce contraction of airway smooth muscle cells first (FIG. 2).
The above experimental results suggest that Yuda 1 is a potent relaxant for ASMCs.
Example 2
(1) Test object
Primary culture of human ASMCs
(2) Laboratory apparatus
Optical magnetic particle torsion cell analysis system (OMTC), living cell workstation, detachable 96-well plate, ultra-clean workbench and CO2A cell culture box, a low-speed centrifuge, a cell counting plate, a constant-temperature water bath kettle, an autoclave and a confocal culture dish.
(3) Experimental procedure
Changes in cell stiffness were detected by optical magnetogranulocyte-twistcell assay after inhibition of Piezo1 in ASMCs followed by YBut 1 treatment. The specific method comprises inoculating cells into a detachable 96-well plate with an inoculation density of 1 × 104After 24h of adherent growth, changing an IT culture medium for 12h, treating ASMCs 48h with siRNA targeting Piezo1 to reduce Piezo1 expression, or adopting GsMTx4(5 mu M) to inhibit Piezo1 activity, adding magnetic microbeads coated with integrin antibodies, and then dynamically detecting the change of cell rigidity along with different concentrations of Udad 1 treatment by using optical magnetic particle torsion cytometry.
The siRNA transfection procedure was performed by first adding 125. mu.L of Opti-MEM and 8. mu.L of si-RNA (5nM) to an EP tube; to another EP tube was added 125. mu.L of Opti-MEM and 6. mu.L of Lipofectamine 3000 reagent. Standing for 5min, adding the latter tube into the former tube, and standing at room temperature for 20 min. The incubated reagents are respectively added into the cells to be transfected, after about 12 hours, the cells are washed 1-2 times by 1 XPBS, replaced by a normal culture medium without antibiotics, and cultured for 24 hours.
The cell rigidity is detected by detecting the cell rigidity in a basic state for 1min, and then adding 10 μ L of Eudaphne 1(1 μ M) to detect the cell rigidity in response to the contraction and relaxation degree of the cells. The detection conditions are as follows: the frequency is 0.3Hz, and the detection time is 5 min.
(4) Results of the experiment
After reducing the activity of Piezo1 and GsMTx4 inhibiting Piezo1 by adopting an RNA interference technology, the result shows that the relaxation effect of Eidao 1 is obviously reduced, and the target of Eidao 1 on Piezo1 plays a relaxation function (figure 3).
Optical magnetic particle torsion cell analysis (OMTC) experiments demonstrated that ewing 1 potently dilates airway smooth muscle cells by activating Piezo 1.
Example 3
(1) Test object
BALB/c mice
(2) Laboratory apparatus
FlexiVent small animal lung function measuring instrument, superclean bench, constant temperature water-bath.
(3) Experimental procedure
The lung function measuring instrument of the FlexiVent small animal is adopted to detect the airway resistance of a normal model mouse and an asthma model mouse, and the airway relaxation function of Eudara 1 is evaluated. The experiment was first randomized into 6 groups: normal control group, asthma model group (ovalbumin treated) control group, Yuda 1 low, medium and high dose groups (0.25mg/kg, 0.5mg/kg, 1mg/kg) and salbutamol group (1mg/kg), 5 per group.
The establishment process of the asthma model is that 200 mu L of ovalbumin sensitizer is injected into the abdominal cavity of each mouse on the 1 st day and the 7 th day respectively, and 100 mu L of ovalbumin sensitizer is injected into the abdominal cavity on the 14 th day; the normal control group is injected with normal saline instead of the sensitizer, and the site and dosage are the same as those of the experimental group. Atomizing and inhaling with 6mL of 1% ovalbumin exciting solution from day 15 to day 21, 1 time per day, 30min each time, and continuously for 7 days; the normal control group was challenged with nebulization with saline instead of 1% ovalbumin.
After the ovalbumin-stressed mice induced the asthma model, on day 22, the treatment groups were separately inhaled by aerosol inhalation of ewing 1(0.25, 0.5, 1mg/kg dose) and salbutamol 1mg/kg, followed by detection of airway resistance in each experimental group using a FlexiVent small animal lung function instrument with the parameters set as: tidal volume 10.72mL/kg (about 250 μ L/time), 150 breaths per minute, and end-of-breath pressure of 3cm H2O；
The detection process of the FlexiVent small animal lung function instrument is that firstly, after a mouse is connected with an animal respirator to breathe stably basically, 50 mu L of normal saline and 30mg/kg of formyl choline are added into an atomization adapter, so that the airway resistance exceeds 4-5 times of a basic value. Subsequently the vasodilator salbutamol or ewa 1 was inhaled by nebulization and the effect of ewa 1 on pulmonary resistance in mice after nebulization was evaluated.
(4) Results of the experiment
After the stimulation with the formyl choline, the atomization inhalation of the albuterol and the Eudapa 1 respectively is carried out, and the result shows that the sole stimulation of 30mg/kg of the methyl choline can increase the airway resistance by 480 percent (normal group) and 520 percent (asthma group), the airway resistance is obviously reduced by 1mg/kg of the albuterol, and the same concentration of the Eudapa 1 has the similar relaxation capacity of the albuterol in the asthma group, which indicates that the Eudapa 1 can also relax airway smooth muscle strongly at the animal level (figure 4).
The lung function experiment of the mouse proves that the Youda 1 can relax the airway smooth muscle of the mouse strongly.
Aiming at the compound mediating the Piezo1 activation, which is mainly Eudar 1, the ASMCs can be remarkably relaxed by detecting 1 muM concentration Eudar 1 by adopting an optical magnetic particle torsion cell assay (OMTC), and the ASMCs can reach about 30 percent. Subsequently, the diastolic effect EC of Euda 1 on ASMCs was found50The value was 7.62. mu.M. Further comparison of the vasodilatory effects of ewda 1 and the classical ASMCs vasodilators Isoproterenol (ISO) and salbutamol on ASMC revealed that ewda 1 was similar to the vasodilatory effects of ISO and salbutamol at the same concentrations, indicating that ewda 1 is a potent ASMCs relaxer.
The invention firstly reveals that the Eudara 1 can activate Piezo1 and can effectively relax airway smooth muscle cells, and the relaxation degree of the Eudara 1 is close to that of isoproterenol and salbutamol. The Eudara 1 is suggested to be used for preparing the medicine for relaxing the airway smooth muscle and the airway smooth muscle relaxing agent, thereby being used for treating asthma, chronic obstructive pulmonary diseases and the like and having wide application prospect.
It should be noted that the above-mentioned embodiments are only for illustrating the technical solutions of the present invention and not for limiting, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, which should be covered by the claims of the present invention.
Claims (10)
- Use of Yoda1 as active ingredient for the preparation of an airway smooth muscle relaxant characterized in that: the structure of Yoda1 is shown in formula I:
- 2. the use of claim 1, wherein: the Yoda1 relaxed airway smooth muscle cells by targeting the mechanosensitive ion channel, Piezo 1.
- The application of Yoda1 as an active ingredient in preparing a medicine for relaxing airway smooth muscle is characterized in that: the structure of Yoda1 is shown in formula I.
- 4. Use according to claim 3, characterized in that: the Yoda1 relaxes airway smooth muscle cells via the Piezo1 receptor.
- 5. Use according to claim 3, characterized in that: the medicine for relaxing airway smooth muscle is a medicine for treating asthma.
- 6. A pharmaceutical composition for relaxing airway smooth muscle, which is characterized in that: at least comprises a compound with a structural formula shown in a formula I.
- 7. A pharmaceutical formulation for relaxing airway smooth muscle, comprising: contains a safe and effective amount of a compound with a structural formula shown in a formula (I) and the balance of a pharmaceutically acceptable carrier.
- 8. The pharmaceutical formulation of claim 7, wherein: the pharmaceutical preparation is injection or spray.
- 9. The pharmaceutical formulation of claim 8, wherein: in the injection, the pharmaceutically acceptable carrier is phosphate buffer solution or normal saline.
- 10. A pharmaceutical formulation according to any one of claims 7 to 9, wherein: the pharmaceutical preparation for relaxing airway smooth muscle is a pharmaceutical preparation for treating asthma.
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