Application of beta-adrenergic receptor antagonist in preparation of anti-aging medicines, health care products or cosmetics

Abstract

The invention provides an application of a beta-adrenergic receptor antagonist in preparation of a medicine, a health care product or a cosmetic for treating and resisting aging. The beta-adrenergic receptor antagonist is any one or a combination of more than two of PubChem 25602667, PubChem 93604753, PubChem 40987983, PubChem 44173546, PubChem 28939663, PubChem 8083224 and PubChem 42907997. The invention further provides a preparation method of the beta-adrenergic receptor antagonist. The beta-adrenergic receptor antagonist is similar to adrenergic in structure and is a beta2 adrenergic receptor ligand, the senescence promoting effect of adrenergic is slowed down by antagonizing a beta2 adrenergic receptor, a new treatment choice is provided for senescence relieving, and the beta-adrenergic receptor antagonist has important practical application value in the fields of medicine and anti-senescence.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine and relates to an anti-aging drug, specifically an application of a beta-adrenergic receptor antagonist in the preparation of anti-aging drugs, health products or cosmetics. Background Art

[0002] With the improvement of medical technology, the average life expectancy of human beings has gradually increased, and the global aging situation has become increasingly serious. Therefore, it is imperative to deeply explore the mechanism of aging and explore effective anti-aging strategies. Currently, there are many types of anti-aging drugs, such as rapamycin, acarbose, metformin and dasatinib.

[0003] Aging is a systemic and systemic process, and antagonizing aging also requires targeting organs and systems throughout the body. β-adrenergic receptors are widely distributed in the human body, and their ligands, catecholamines, are both hormones and neurotransmitters, and participate in various physiological activities of the body. It is well known that the aging process is accompanied by overexcitement of the sympathetic system and hyporesponsiveness of the adrenergic system. At present, β-adrenergic receptor antagonists are rarely used in the anti-aging field. There is a lack of sufficient clinical evidence to prove their effectiveness in anti-aging and preventing and treating aging-related diseases, and there are safety issues for long-term use. Therefore, the development of new β-adrenergic receptor antagonists and the exploration of their anti-aging effects are of great significance to the research on delaying aging. Summary of the invention

[0004] In view of the above technical problems in the prior art, the present invention provides an application of a β-adrenergic receptor antagonist in the preparation of anti-aging drugs, health products or cosmetics. The application of the β-adrenergic receptor antagonist in the preparation of anti-aging drugs, health products or cosmetics is to solve the technical problem of poor anti-aging effect of drugs in the prior art.

[0005] The present invention discloses an application of a beta-adrenergic receptor antagonist in the preparation of a drug, a health product or a cosmetic for treating anti-aging. The beta-adrenergic receptor antagonist is any one of PubChem_25602667, PubChem_93604753, PubChem_40987983, PubChem_44173546, PubChem_28939663, PubChem_8083224 and PubChem_42907997, or a combination of two or more thereof. The structural formula of PubChem_25602667 is:

[0006]

[0007] The structural formula of PubChem_93604753 is,

[0008]

[0009] The structural formula of PubChem_40987983 is,

[0010]

[0011] The structural formula of PubChem_44173546 is,

[0012]

[0013] The structural formula of PubChem_28939663 is,

[0014]

[0015] The structural formula of PubChem_8083224 is,

[0016]

[0017] The structural formula of PubChem_42907997 is,

[0018]

[0019] The present invention provides an anti-aging medicine, health product or cosmetic, comprising a beta-adrenergic receptor antagonist, wherein the beta-adrenergic receptor antagonist is any one of PubChem_25602667, PubChem_93604753, PubChem_40987983, PubChem_44173546, PubChem_28939663, PubChem_8083224 and PubChem_42907997, or a combination of two or more thereof.

[0020] The structural formula of PubChem_25602667 is,

[0021]

[0022] The structural formula of PubChem_93604753 is,

[0023]

[0024] The structural formula of PubChem_40987983 is,

[0025]

[0026] The structural formula of PubChem_44173546 is,

[0027]

[0028] The structural formula of PubChem_28939663 is,

[0029]

[0030] The structural formula of PubChem_8083224 is,

[0031]

[0032] The structural formula of PubChem_42907997 is,

[0033]

[0034] Furthermore, the anti-aging medicine, health product or cosmetic also contains a pharmaceutically acceptable carrier and / or excipient.

[0035] In order to discover and verify the above group of compounds, the present invention adopts the following technical scheme:

[0036] In a first aspect of the present invention, a druggable virtual compound library is established based on the PubChem database.

[0037] In the second aspect of the present invention, pharmacophore screening is performed on a druggable virtual compound library based on an existing pharmacophore generation model for beta receptor antagonists.

[0038] In a third aspect of the present invention, molecules selected through pharmacophore screening are docked with β2-adrenergic receptors, and molecules with better docking results than adrenaline are derived as docking molecule sets.

[0039] In the fourth aspect of the present invention, the molecules in the docking molecule set were subjected to pharmacokinetic and toxicity analysis, and 7 compounds with potential anti-aging functions that are similar to adrenaline were obtained, including PubChem_25602667, PubChem_93604753, PubChem_40987983, PubChem_44173546, PubChem_28939663, PubChem_8083224, and PubChem_42907997.

[0040] The present invention provides a group of compounds similar to adrenaline, which are β-adrenaline receptor antagonists, and can slow down the aging effect of adrenaline by antagonizing β2 adrenaline receptors, thereby restoring the proliferation ability of senescent cells.

[0041] Specifically, the group of compounds having similarity to adrenaline are used in the anti-aging drug in an amount of 15 mg / kg / d.

[0042] Compared with the existing technology, the technical effect of the present invention is positive and obvious. The present invention uses virtual screening to select 7 new β-adrenergic receptor antagonists with anti-aging potential from a large number of drug compounds, providing a new idea for the anti-aging research of β-adrenergic receptor antagonists. And its anti-aging effect has been verified through cell experiments and animal experiments, which brings new opportunities for deepening the understanding of the aging mechanism, exploring more effective methods to delay aging, and better responding to the challenges of an aging society. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0044] Figure 1 It is a schematic diagram showing the changes in the growth and proliferation ability of senescent cells induced by isoproterenol after being incubated with a group of compounds similar to adrenaline in the application of the present invention in anti-aging.

[0045] Figure 2 The present invention is an application of a group of compounds similar to adrenaline in anti-aging, and a schematic diagram of survival analysis of rapidly aging mice treated with a group of compounds similar to adrenaline. DETAILED DESCRIPTION

[0046] In order to better understand the technical solution of the present invention, the embodiments of the present invention are described in detail below with reference to the accompanying drawings.

[0047] It should be clear that the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0048] Example 1

[0049] The invention discloses the application of a group of compounds similar to adrenaline in anti-aging. The compounds are beta-adrenaline receptor antagonists and have anti-aging effects.

[0050] 1. A druggable virtual compound library was established based on the PubChem database. The specific druggable principles were as follows: numhydrogen acceptors≤10, num hydrogen donors≤5, molecular weight≤500, logp≤5, atom counts between 20 and 70, molar refractivity in the range of 40 to 130, number of rotatable bonds≤10, and total polar surface area≤140.

[0051] 2. Collect existing β-receptor antagonists as active molecule input Maestro software generates several pharmacophore models. Based on the default scores within the software, the three pharmacophore models with the best fit are selected, and pharmacophore screening is performed on the druggable virtual compound library. Molecules with a phase screen score greater than 1 are exported as molecules that pass the pharmacophore screening.

[0052] 3. Use the autodock vina software to perform molecular docking between the molecules that pass the pharmacophore screening and the β2-adrenergic receptor, output the binding free energy between the molecule and the receptor, and export the molecules with binding free energy better than adrenaline as the docking molecule set.

[0053] 4. Upload the molecules in the docking molecule set to the ADMET analysis website, exclude compounds that are potentially toxic, cannot be absorbed by cells, have too low a distribution in the human body, and cannot be excreted by the human body, and finally obtain 7 compounds with potential anti-aging functions that are similar to adrenaline, including PubChem_25602667, PubChem_93604753, PubChem_40987983, PubChem_44173546, PubChem_28939663, PubChem_8083224, and PubChem_42907997.

[0054] The above seven substances are introduced as follows:

[0055] PubChem_25602667, molecular formula is C 17 H 26N2O3, IUPAC Name is 4-[(2S)-3-(2-tert-butylpheno xy)-2-hydroxypropyl]piperazin-2-one, included in PubChem database,

[0056]

[0057] PubChem_93604753, molecular formula is C 15 H 22 N2O3, IUPAC Name is 4-[(2S)-3-(3,5-dimethylpheno xy)-2-hydroxypropyl]piperazin-2-one, included in PubChem database;

[0058]

[0059] PubChem_40987983, molecular formula is C 16 H 23 N3O2, IUPAC Name is (2S)-1-[2-[(2-methylphenyl)methylamino]-2-oxoethyl]piperidine-2-carboxamide, included in PubChem database;

[0060]

[0061] PubChem_44173546, molecular formula is C 14 H 18 N2O4, IUPAC Name is (2S)-5-amino-5-oxo-2-(3-pheny lpropanoylamino)pentanoic acid, also known as N-hydrocinnamoyl-L-glutamine (N-hydroxycinnamoyl-L-glutamine), included in the PubChem database;

[0062]

[0063] PubChem_28939663, molecular formula is C 15 H 20N2O4, IUPAC Name is (2S)-5-amino-5-oxo-2-(4-pheny lbutanoylamino)pentanoic acid, also known as 4-Phenylbutyrylglutamine (4-phenylbutyrylglutamine), PBGN, is the metabolite of phenylbutyric acid in the human body, included in the PubChem database;

[0064]

[0065] PubChem_8083224, molecular formula is C 20 H 21 FN4O4, IUPAC Name is N-[(2S)-5-amino-1,5-dioxo-1-[2-(2-phenylacetyl)hydrazinyl]pentan-2-yl]-4-fluorobenzamide, included in PubChem database;

[0066]

[0067] PubChem_42907997, molecular formula is C 20 H 21 ClN4O4, IUPAC Name is N-[5-amino-1,5-dioxo-1-[2-(2-phenylacetyl)hydrazinyl]pentan-2-yl]-4-chlorobenzamide, included in PubChem database.

[0068]

[0069] 5. This group of compounds that have similarities to adrenaline are used as raw materials for preparations that restore the proliferation capacity of aging cells.

[0070] 6. This group of compounds similar to adrenaline are used in the anti-aging drug in an amount of 15 mg / kg / d.

[0071] Example 2 CCK8 (Cell Counting Kit 8) experiment.

[0072] Using MCE's CCK8 kit, human umbilical vein endothelial cells (HUVEC) were treated with isoproterenol for 24 hours after inoculation to cause cell senescence and construct a senescent cell model. Then, each compound (purchased from EnamineStore) was treated with different concentrations: 0uM, 10uM, 15uM, 20uM, and 30uM for 24 hours, and the cell growth and proliferation ability was detected. After adding PBS around a circle around the 96-well cell culture plate, an appropriate number of cells (volume of 100μL) were inoculated in the inner circle of the 96-well cell culture plate so that the cell fusion degree was controlled at about 70% after 24 hours. Three replicate wells were prepared for each drug at different concentrations. During the experiment, the CCK8 solution was taken out of the refrigerated and frozen combination low-temperature storage box in advance and equilibrated to room temperature. 10μL of CCK8 solution was added to each well (to avoid bubbles), and the 96-well cell culture plate was placed in the incubator for 1 hour. The absorbance at 450nm was detected and recorded using an enzyme reader.

[0073] Figure 1 The results showed that the survival rate of cells after isoproterenol aging modeling was increased compared with the control group (aging cells without additional treatment) after being treated with this group of compounds similar to adrenaline, indicating that this group of compounds similar to adrenaline can restore the proliferation ability of aging cells to a certain extent.

[0074] Example 3

[0075] Senescence-Accelerated Mouse-Prone (Senescence-Accelerated Mouse-Prone, SAMP8) (purchased from Jiangsu Wukong Biotechnology Co., Ltd.) and this group of compounds similar to adrenaline were used to intervene in the experiment.

[0076] Take 0.5g of CMC-Na and mix with 99.5g of NaCl injection to make CMC-Na solution for later use.

[0077] 60 mL of CMC-Na solution with a mass percentage concentration of 0.5% was used to dissolve corresponding volumes of the seven compounds, respectively, to prepare solutions (10 mM) of the seven drugs.

[0078] The body weight of SAMP8 mice required for the experiment was weighed, and the experimental group (n=7) was injected with each drug at a dose of 15 mg / kg / d, and the control group (n=7) was injected with an equal amount of solvent. After continuous administration for 30 days, the status of the mice was observed and recorded.

[0079] Figure 2 It showed that feeding these seven drugs to rapidly aging mice separately could significantly prolong the lifespan of the mice and improve the survival rate of rapidly aging mice.

[0080] The embodiments of the present invention are described in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method of the present invention and its core idea. At the same time, for those skilled in the art, according to the idea of ​​the present invention, there will be changes in the specific implementation methods and application scope. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. A use of a β-adrenergic receptor antagonist in the preparation of anti-aging drugs, health products or cosmetics, characterized in that: The β-adrenergic receptor antagonist is any one of PubChem_25602667, PubChem_93604753, PubChem_40987983, PubChem_44173546, PubChem_28939663, PubChem_8083224, and PubChem_42907997, or a combination of two or more thereof. The structural formula of PubChem_25602667 is: The structural formula of PubChem_93604753 is, The structural formula of PubChem_40987983 is, The structural formula of PubChem_44173546 is, The structural formula of PubChem_28939663 is, The structural formula of PubChem_8083224 is, The structural formula of PubChem_42907997 is, 2. An anti-aging drug, health product or cosmetic, characterized in that: Containing a β-adrenergic receptor antagonist, wherein the β-adrenergic receptor antagonist is any one of PubChem_25602667, PubChem_93604753, PubChem_40987983, PubChem_44173546, PubChem_28939663, PubChem_8083224, and PubChem_42907997, or a combination of two or more thereof; The structural formula of PubChem_25602667 is, The structural formula of PubChem_93604753 is, The structural formula of PubChem_40987983 is, The structural formula of PubChem_44173546 is, The structural formula of PubChem_28939663 is, The structural formula of PubChem_8083224 is, The structural formula of PubChem_42907997 is, 3. An anti-aging medicine, health product or cosmetic according to claim 2, characterized in that: The anti-aging medicine, health product or cosmetic also contains a pharmaceutically acceptable carrier and / or excipient.

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