CN107335058B - New application of 2, 6-disubstituted pyridine-4-thiocarboxamide - Google Patents

New application of 2, 6-disubstituted pyridine-4-thiocarboxamide Download PDF

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CN107335058B
CN107335058B CN201710643752.3A CN201710643752A CN107335058B CN 107335058 B CN107335058 B CN 107335058B CN 201710643752 A CN201710643752 A CN 201710643752A CN 107335058 B CN107335058 B CN 107335058B
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thiocarboxamide
bitter
bitter taste
disubstituted pyridine
taste
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CN107335058A (en
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刘忠
马冬磊
揭辉洋
李满妹
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Jinan University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/045—Organic compounds containing nitrogen as heteroatom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/055—Organic compounds containing sulfur as heteroatom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Abstract

The invention belongs to the technical field of medicines and the field of foods, and particularly relates to a new application of 2, 6-disubstituted pyridine-4-thiocarboxamide in preparation of bitter suppression medicines or foods. The invention discloses that the 2, 6-disubstituted pyridine-4-thiocarboxamide has an inhibiting effect on a bitter taste receptor hTAS2R38 for the first time, and the inhibiting effect is obvious. The 2, 6-disubstituted pyridine-4-thiocarboxamide can be independently applied to preparing bitter suppressing drugs and can also be used as a drug preparation additive, the bitter of the drugs is reduced by compounding the compounds, and any preparation form suitable for clinical use can be prepared, including tablets, powder, oral liquid or spray and the like. Meanwhile, the product can be used as food additive to adjust the taste of food.

Description

New application of 2, 6-disubstituted pyridine-4-thiocarboxamide
Technical Field
The invention belongs to the technical field of medicines and the field of foods, and particularly relates to a new application of 2, 6-disubstituted pyridine-4-thiocarboxamide in preparation of bitter suppression medicines or foods.
Background
Bitter taste is one of the basic tastes of the human body. In recent years, various kinds of foods, beverages, and the like added with functional components have been developed due to the increase of health consciousness of consumers, and so-called functional components having useful effects on the human body generally have bitter taste, which inevitably causes a decrease in taste preference, resulting in a decrease in product appeal. Although the bitterness of some foods, such as beer, coffee, dark chocolate, red wine, etc., can make them delicious, in many cases, the bitterness of foods is unacceptable, and if the bitterness is too strong, it is accompanied by unpleasant or even aversion. In the pharmaceutical industry, many drugs have certain limitations in clinical application and formulation development due to their bitter taste, and most active pharmaceutical ingredients with poor taste also have bitter taste. The taste of the medicine is an important factor influencing the medication compliance of patients, any preparation prescription has better taste than similar competitive products, especially the medicine for pediatrics, and the medication compliance can be greatly improved if the taste is easy to accept by children. Therefore, how to effectively remove the bitter taste, improve the compliance of patients and the value of products becomes one of the key contents in the research and development process of medicines and foods.
To reduce the unpleasant taste perception associated with bitterness, bitterness masking techniques are required to reduce the bitterness intensity of the product. On the basis of not influencing the efficacy of the bitter substances, the proper masking of the bitter taste of the substances has wide practical significance. The traditional method for masking the bitter taste of food is to add a large amount of cane sugar, salt or some high-fat substances, but with the improvement of living standard, people pay more attention to health preservation and health care, and the traditional method can not meet the requirements of people on low salt, low calorie and low sugar content of food. In the pharmaceutical preparation process, the bitter taste is often masked by means of coating, capsule wrapping, inclusion, microencapsulation and the like, but the technologies are only suitable for solid preparations, chemical pharmaceutical preparations with single components and the like and cannot be applied to large-dose and multi-component pharmaceutical preparations. Traditional Chinese medicine is a typical bitter medicine, the strong unpleasant smell and taste of the traditional Chinese medicine cause the great weakening of the advantages of traditional Chinese medicine treatment, and the stimulation of bitter taste of the traditional Chinese medicine is usually reduced by adopting methods of increasing the sweet taste and the fragrance of the traditional Chinese medicine. However, many drugs have high bitterness, and the purpose of masking bitterness can be fundamentally achieved only through effective inhibition. Therefore, it is an urgent need to find a bitter taste inhibitor that is safe, highly effective, stable, and inexpensive.
Studies have shown that bitter taste is perceived through G protein-coupled receptors (GPCRs) and bitter taste receptors located on taste cell membranes (TAS2Rs or T2 Rs). GPCRs are the most important receptors for taste, smell, tropism, immunity, endocrine and nerve conduction substances, and play an important role in metabolism of substances, energy and cell signaling. The bitter taste receptor is a polypeptide chain with 7 transmembrane helical structures, belongs to a member of GPCRs superfamily, has found 25 subtypes in human body, can recognize bitter substances with various structures, and is closely related to the perception of bitter taste of the body. After bitter substance is combined with bitter receptor protein, signal is transduced into cell by intracellular messenger, calcium ion channel on cell membrane is opened to make calcium ion flow in cell or combined with calcium ion channel on endoplasmic reticulum membrane to release calcium ion, so that the calcium ion concentration in cell is raised, the cell membrane is depolarized to excite neuron after nerve cell is burst, excitatory signal is integrated by nerve centre after entering solitary nucleus, and finally the bitter taste is sensed by body. Bitter taste receptor inhibitors are compounds that reduce or eliminate the bitter taste of bitter substances, primarily by blocking bitter taste receptors, blocking bitter taste signaling, and the like. The inhibitor and the receptor agonist compete for binding sites or cause allosteric phenomenon after binding with the receptor to play a role in suppressing bitter taste.
Greene et al, in the "Probenecid inhibitors the human bit step receiver tas2R16and supress bit preference of nalcin", propose that Probenecid can inhibit the activity of hTAS2R38 receptor activated by 2 ligands of phenylthiourea or propylthiouracil and the activity of hTAS2R38 receptor activated by barbaloin, and further effectively inhibit the bitter taste of salicin, and lay the foundation for clinically using salicin as bitter inhibitor. However, the inhibition effect of 2, 6-disubstituted pyridine-4-thiocarboxamide on hTAS2R38 bitter taste receptor has not been reported.
Disclosure of Invention
The invention aims to provide a new application of 2, 6-disubstituted pyridine-4-thiocarboxamide in preparing bitter suppression medicaments or foods. The 2, 6-disubstituted pyridine-4-thiocarboxamide provided by the invention has an obvious inhibition effect on a bitter taste receptor hTAS2R 38.
Further, the 2, 6-disubstituted pyridine-4-thiocarboxamide has the following structure:
Figure BDA0001366413620000021
wherein R is1Is a hydrogen atom or an alkyl group, etc., R2Is hydrogen atom or thiocarboxamide.
Further, R in the 2, 6-disubstituted pyridine-4-thiocarboxamide1Is an alkyl group.
Further, the alkyl in the 2, 6-disubstituted pyridine-4-thiocarboxamide is methyl, ethyl, propyl or isopropyl.
Further, the 2, 6-disubstituted pyridine-4-thiocarboxamide is 2-methylpyridine-4-thiocarboxamide, 2-ethylpyridine-4-thiocarboxamide, 2-propylpyridine-4-thiocarboxamide, 2-isopropylpyridine-4-thiocarboxamide or 6-methylpyridine-2, 4-dithioformamide, and has the structure shown as follows:
Figure BDA0001366413620000031
the 2, 6-disubstituted pyridine-4-thiocarboxamide provided by the invention can be independently applied to preparation of bitter suppressing drugs, and can also be used as a drug preparation additive to be compounded to form a composition for reducing the bitter taste of drugs. Meanwhile, the product can be used as food additive to adjust the taste of food. In the pharmaceutical industry, the bitter inhibitor 2, 6-disubstituted pyridine-4-thioformamide can be prepared into any clinically applicable dosage form, such as tablets, capsules, granules, powder, oral liquid, injection, powder injection, injection or spray.
The invention discloses that the 2, 6-disubstituted pyridine-4-thiocarboxamide has an inhibiting effect on a bitter taste receptor hTAS2R38 for the first time, and the inhibiting effect is obvious.
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FIG. 1: effect of 2-propylpyridine-4-thiocarboxamide on the fluorescence intensity of HEK293T cells;
FIG. 2: a concentration-dependent curve of 2-propylpyridine-4-thiocarboxamide for changes in calcium ion concentration;
FIG. 3: sensory evaluation of bitterness inhibition by 2-propylpyridine-4-thiocarboxamide;
FIG. 4: effect of 6-methylpyridine-2, 4-dithioformamide on the fluorescence intensity of HEK293T cells;
FIG. 5: a concentration-dependent curve of 6-methylpyridine-2, 4-dithioformamide for changes in calcium ion concentration;
FIG. 6: sensory evaluation of 6-methylpyridine-2, 4-dithioformamide for suppressing bitterness.
Detailed Description
The present invention is further illustrated by the following specific examples, which are provided for illustrative purposes only and do not limit the scope of the present invention.
The HEK293T cells adopted by the invention are derived from a cell bank of Chinese academy of sciences; the Ga16/gust44 vector used was given by professor Takashi Ueda, university of Nippon Minggu; fluo4-AM was purchased from Molecular Probes; 2-propylpyridine-4-thiocarboxamide, 6-methylpyridine-2, 4-dithioformamide, Propylthiouracil (PROP) were purchased from Sigma. All compound powders were dissolved sufficiently in dimethyl sulfoxide (Sigma) and stored at-20 ℃ until use.
Example 1 inhibition of bitter taste receptor hTAS2R38 function by 2-propylpyridine-4-thiocarboxamide
PROP is an agonist of bitter taste receptor hTAS2R38, and can stimulate and activate bitter taste receptor, resulting in change of calcium ion concentration in cell. Fluo4-AM is an acetyl methyl ester derivative of Fluo4 that can be readily introduced into cells by culture. AM is hydrolyzed by intracellular esterase after entering cells, and the generated Fluo4 is then mixed with calcium ions (Ca)2+) Bind and fluoresce. This study used the pro alone or the pro and 2-propylpyridine-4-carbothioamide (PROP +3) to stimulate HEK293T cells transfected and expressing bitter receptors and to obtain the immediate fluorescence changes by fluorescence microscopy.
The research constructs an expression vector of a bitter taste receptor hTAS2R38, and adopts an overlap extension PCR technology to splice the first 39 amino acid residue sequences of the N end of rhodopsin and the hTAS2R38 sequence together so as to enhance the positioning of the hTAS2R38 on the surface of an expression cell. In addition, the bitter taste receptor also requires the expression of the coupled protein Ga16/gust44 for its function in cells. HEK293T cells were cultured in DMEM complete medium and placed at 37 ℃ in 5% CO2In the cell culture box, digestion and passage are carried out once in 2-3 days, and cells in a logarithmic growth phase are taken for experiment. HEK293T cells in logarithmic growth phase were plated in 96-well plates at approximately 4X 10 per well4～5×104Placing the cells at 37 deg.C and 5% CO2Culturing in an incubator overnight; after the cells are completely attached to the wall, co-transfecting the hTAS2R38 and Ga16/gust44 plasmid DNA into the cells, culturing for 4-6 h, removing a serum-free culture medium, culturing by using a complete culture medium, removing the culture medium after 24h, and washing the cells once by using a detection buffer solution; adding 50 mu L of Fluo4-AM with the concentration of 5 mu M into each well, and removing Fluo4-AM after incubating for 1h at 37 ℃; add 50. mu.L of assay buffer to each well and add 50. mu.L of different concentrationsAdding 2-propylpyridine-4-thiocarboxamide into a 96-well plate, and observing the change trend of the fluorescence intensity in the cells within 180s by using a fluorescence microscope.
The fluorescence Image data is analyzed by adopting Image J software, other data is analyzed by adopting GraphPad prism5.0 software, and each experiment is repeated for 3 times; comparisons between groups were performed using independent samples t-test, indicating P <0.01, and differences were significant.
Figure BDA0001366413620000041
F-fluorescence intensity at each time point
F0Initial fluorescence intensity
As can be seen from fig. 1 and 2: inhibition of bitter taste receptor hTAS2R38 function by 2-propylpyridine-4-thiocarboxamide. As shown in FIG. 1, 2-propylpyridine-4-thioformamide has a remarkable effect of reducing the intracellular fluorescence intensity, i.e., can remarkably inhibit intracellular Ca2+The concentration is increased, and the inhibition rate reaches 51.4 percent by comparing with the maximum fluorescence intensity value, which indicates that 2-propylpyridine-4-thiocarboxamide is an effective antagonist of bitter taste receptor hTAS2R 38. FIG. 2 shows that 2-propylpyridine-4-thiocarboxamide can inhibit PROP-induced expression of intracellular Ca from hTAS2R38 in a concentration-dependent manner2+The concentration is increased; when the concentration reached 50. mu.M, the curve tended to be flat, with half the Inhibition (IC)50) 16.99. mu.M.
Example 2 sensory evaluation of 2-propylpyridine-4-carbothioamide to inhibit bitterness
The study verifies the bitter taste inhibition effect of the bitter receptor inhibitor through human body bitter taste perception. From the subject group, 20 healthy volunteers (10 male and 10 female) who were interested in the sensory evaluation test and had good speech expression ability and basic sensory discrimination ability were selected as subjects, and informed consent was signed before the test.
Preparing bitter substance and bitter inhibitor solution. Bitter substances and their concentrations: potassium chloride, saccharin sodium, caffeine, quinine hydrochloride, artificial bezoar (commercial product, non-pure product), and reference food additive with different bitter taste intensity of the above five bitter substances set at final concentrations of 1000, 15000, 2500, 500, and 25ppm respectively; bitter taste inhibitors to be tested and their concentrations: r-aminobutyric acid (a known bitterness inhibitor, as a control) and 2-propylpyridine-4-carbothioamide. According to the specified standard of the amount of the food additive, the concentration of the bitter taste inhibitor r-aminobutyric acid to be detected is determined to be 200ppm, and the concentration of the 2-propylpyridine-4-thiocarboxamide is determined to be 200ppm according to the half-inhibitory concentration and the available dose. Preparing a bitter inhibitor solution in a sodium salt form, accurately weighing 0.2g of r-aminobutyric acid, dissolving the r-aminobutyric acid in 100mL of purified water, adding sodium bicarbonate until the pH value of the solution is 7, and pouring the solution into a 1000mL volumetric flask to fix the volume to prepare the r-aminobutyric acid (sodium salt) solution with the concentration of 200 ppm. Adding the bitter inhibitor solution into the bitter substance in equal volume to obtain mixed solution. 0.2g of 2-propylpyridine-4-thiocarboxamide was dissolved using the same dissolution method, and the 2-propylpyridine-4-thiocarboxamide solution and the bitter substance were mixed to form a mixed solution.
The bitterness intensity of the mixed solution was tasted by a sensory evaluator, and pure water was used as a blank control experiment, and the bitterness inhibitor r-aminobutyric acid was known as a positive control. The sensory evaluation personnel keeps the tasted mixed solution to continuously rotate in the mouth but not swallow, so that the samples flow through each part of the tongue, a large amount of clear water is needed for mouth rinsing after one sample is tested, and the tasting interval of two adjacent sample solutions needs to be more than 15min, thereby ensuring the accuracy and reliability of the test result. The evaluation results are expressed as numerical values, each experiment is repeated 3 times, and the average value is finally calculated. The scores were 0-10 points, with reference to the scoring criteria in the table below. Data were analyzed using GraphPad prism5.0 software, with 3 replicates per experiment; comparisons between groups were performed using independent samples t-test, indicating P <0.01, and differences were significant. Bitterness scores were as follows in table 1:
TABLE 1 evaluation criteria for bitterness degree
Intensity of bitterness Corresponding score
Without bitter taste 0-2
Is bitter 2-4
Bitter taste 4-6
Is very bitter 6-8
Extremely bitter 8-10
As can be seen from fig. 3: the 2-propylpyridine-4-thiocarboxamide has a remarkable effect of inhibiting bitter taste, the bitter taste inhibiting capability of the 2-propylpyridine-4-thiocarboxamide is better than that of the positive drug namely r-aminobutyric acid, and the bitter taste inhibiting capability of the 2-propylpyridine-4-thiocarboxamide is different for different bitter taste stimulating substances.
Example 3 inhibition of bitter taste receptor hTAS2R38 function by 6-methylpyridine-2, 4-dithioformamide
This study stimulated HEK293T cells transfected and expressing bitter taste receptors with PROP alone or with PROP and 6-methylpyridine-2, 4-dithioformamide (PROP + 5).
The study procedure was similar to example 1.
The difference from example 1 is that 2-propylpyridine-4-carbothioamide is replaced by 6-methylpyridine-2, 4-carbodithioamide.
As can be seen from fig. 4 and 5: 6-methylpyridine-2, 4-dithioformamideInhibition of bitter taste receptor hTAS2R38 function. Fig. 4 shows that 6-methylpyridine-2, 4-dithioformamide can significantly inhibit the change of intracellular calcium ion concentration caused by PROP, and the inhibition rate reaches 66.0%, which indicates that 6-methylpyridine-2, 4-dithioformamide has a good inhibition effect on bitter taste receptors. As can be seen in FIG. 5, 6-methylpyridine-2, 4-dithioformamide has a concentration-dependent inhibitory effect on the increase in PROP-stimulated calcium ion concentration, and when the concentration reaches 50. mu.M, the inhibition curve begins to flatten, and the IC thereof becomes flat50The value was 13.99. mu.M.
Example 4 sensory evaluation of 6-methylpyridine-2, 4-dithioformamide for suppressing bitterness
The study procedure was similar to example 2.
The difference from example 2 is that 2-propylpyridine-4-carbothioamide is replaced by 6-methylpyridine-2, 4-carbodithioamide.
As can be seen from fig. 6: 6-methylpyridine-2, 4-dithioformamide has different degrees of inhibition effects on the bitter taste of different substances, has significant inhibition effects on the bitter taste of potassium chloride, saccharin sodium, quinine hydrochloride and caffeine, and has better bitter taste inhibition effect than that of a positive medicament gamma-aminobutyric acid.
While the invention has been described in further detail with reference to specific preferred embodiments thereof, it should be understood that the invention is not limited to the specific embodiments thereof. For those skilled in the art to which the invention pertains, several simple deductions or substitutions may be made without departing from the spirit of the invention, and these deductions or substitutions should be considered as the protection scope of the invention.

Claims (1)

  1. New use of 2-propylpyridine-4-thiocarboxamide or 6-methylpyridine-2, 4-dithioformamide in the preparation of bitter taste inhibitor drugs or foods;
    the structures of the 2-propylpyridine-4-thiocarboxamide or 6-methylpyridine-2, 4-dithioformamide are respectively shown as the following figures:
    Figure DEST_PATH_IMAGE002
    。
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