JP7612364B2 - Smell suppressant - Google Patents

Description

The present invention relates to an odor sense suppressant.

Smells play an important role in enriching our daily lives. For example, the smell of cooking provides a rich flavor, and the smell of everyday products gives a sense of cleanliness and other pleasant sensations. On the other hand, unpleasant smells are also important. Smells play a major role in quickly letting us know when our health or hygiene is impaired. However, there are many people who find the smell of perfume or fabric softener worn by others unpleasant. There have also been reported cases of olfactory hypersensitivity caused by illness or stress, and these patients experience stress on a daily basis because they are sensitive to all kinds of odors, and in severe cases, this can even interfere with their daily lives.

Most odorants are volatile low-molecular-weight organic compounds with molecular weights of approximately 30 to 300. These odorants vary not only in the quality of their odor but also in their chemical structures, and in molecular biology research, they are often classified based on their chemical structures. For example, Non-Patent Document 1 classifies 125 types of odorants into 13 groups: amines, thiols, alcohols, esters, ethers, aldehydes, cyclic alkanes, terpenes, vanillins, camphors, azines, musks, and ketones and others. Patent Document 1 also classifies odorants into nine groups: amines, alcohols, aldehydes, ketones, acids, esters, benzenes, vanillin-like compounds, and lactones.

Odorants are recognized by olfactory receptors in the olfactory nerve cells that are spread in the deepest part of the nasal cavity. The olfactory receptors bind to and activate odorants, causing electrical excitation in the olfactory nerve cells. This electrical excitation is transmitted to the higher brain via neural connections, and the odor is perceived. In humans, there are approximately 400 types of genes that code for olfactory receptors. This large number of receptors is the molecular basis that enables the detection of the various odors mentioned above. Each of these approximately 400 types of olfactory receptors is expressed in a different olfactory nerve cell. On the other hand, olfactory nerve cells that express the same olfactory receptor converge to the same specific area in the olfactory bulb where the axon is projected. For this reason, information on which olfactory receptor is activated in the nasal cavity is reflected in geometric information, that is, the area of the olfactory bulb that fires, and is transmitted to the higher brain area without being lost. In this way, it is thought that information on the combination of olfactory receptors that are activated for each odorant is transmitted to the higher brain area, resulting in differences in the quality of the odor.

Knowledge has been accumulating about the relationship between odors and the olfactory receptors involved in their recognition. According to these findings, olfactory receptors generally selectively recognize structurally similar odorants. For example, Non-Patent Document 1 suggests that about 45% of the approximately 1,000 olfactory receptors in mice recognize only one group of odorants that are classified into 13 groups based on their chemical structure. On the other hand, Non-Patent Document 1 suggests that 13.4% of olfactory receptors recognize odorants in groups 5 to 9, and in particular 1.8% recognize odorants in groups 10 to 12, which is an extremely wide range of odorants structurally. Olfactory receptors that recognize such a wide range of odorants are called broadly tuned olfactory receptors. Non-Patent Document 1 lists mouse Olfr42 as a representative broadly tuned olfactory receptor. Non-Patent Document 2 also lists OR2W1, the human homologue of Olfr42, as a broadly tuned olfactory receptor. Previously, several hypotheses have been proposed regarding the role of broadly tuned olfactory receptors (Non-Patent Document 2), but these hypotheses have not been verified.

Recently, a BT receptor single response model was constructed that selectively activates only OR2W1, one of the broadly tuned olfactory receptors (BT receptors), and the role of the BT receptor was verified. Patent Document 2 reports that enhancing the activity of the BT receptor makes it possible to sense the odor of various odorants more sensitively or more strongly, and suggests that the BT receptor transmits information about the odor intensity, rather than the odor quality, of various odorants. Patent Document 2 also describes that a substance that controls the response of the BT receptor can be used as a substance that controls the sense of smell regardless of the type of odor.

International Publication No. 2015/020158 International Publication No. 2018/142961

J Neurosci, 31:9179-91, 2011 Proc Natl Acad Sci USA, 112:14966-71, 2015

It is desirable to make daily life more comfortable by appropriately controlling the sense of smell. The present invention relates to an odor sense suppressant that can suppress the sense of smell regardless of the type of odor.

The present inventors have discovered substances that inhibit the broadly tuned olfactory receptor OR2W1. These substances are able to suppress the sense of smell for various odorants, regardless of the type of odor, through the inhibition of OR2W1.

Therefore, the present invention provides an odor sense suppressant that contains at least one active ingredient selected from the group consisting of ambrettolide, muscone, and damascenone, and that suppresses the odor sense regardless of the type of odor.

The odor sense suppressant of the present invention inhibits the broadly tuned olfactory receptor OR2W1, thereby suppressing the odor sense for various odors regardless of the type of odor.

Inhibitory activity of OR2W1 by ambrettolide, muscone and damascenone. Data show the mean and standard error of the response inhibition level of OR2W1 from three experiments. A response inhibition level value smaller than 1 indicates a tendency to inhibition, and a smaller response inhibition level value indicates stronger inhibition. Inhibitory effect of ambrettolide, muscone, and damascenone on indole odor. Data are the average values of the evaluations by four panelists, and error bars indicate standard error. The effect of ambrettolide, muscone, and damascenone on suppressing PEA odor. Data are the average values of evaluations by three panelists, and error bars represent standard error. Suppression effect of various odors by ambretteride below the detection threshold. A panel of 6 to 7 experts rated the malodor of the test fabrics on a 5-point scale by pairwise comparison of the control fabric (malodor only, no ambretteride) and the test fabrics (malodor + ambretteride). The number of people who selected each malodor level is shown in the table.

As used herein, "suppression of olfactory sense" refers to the phenomenon in which an individual's sensitivity to an odor decreases. The strength of sensitivity to an odor can be evaluated based on the detection strength or detection threshold (sensitivity) of the odor. For example, if the detection strength for a target odor decreases or the detection threshold increases (or the detection sensitivity decreases), it is determined that sensitivity to the target odor has decreased, and at this point the odor sense for the target odor is suppressed.

In this specification, a "substance that causes suppression of the sense of smell" (so-called an odor sense suppressant) is a substance that, when used in combination with a target odorant (e.g., used simultaneously with or prior to the target odorant), causes a subject to sense the target odor weaker or detect it with lower sensitivity (at a higher concentration threshold) than when the target odorant is applied alone. A substance that causes suppression of the sense of smell may itself have an odor.

In this specification, a "Broadly Tuned Olfactory Receptor" (also referred to as "BT receptor" in this specification) is an olfactory receptor that responds to multiple types of odorants having different odors, unlike many olfactory receptors that selectively recognize a small number of specific odorants. More specifically, a BT receptor refers to an olfactory receptor that responds to multiple odorants belonging to different structural classes. Examples of structural classes of odorants include amines, thiols, alcohols, esters, ethers, aldehydes, cyclic alkanes, terpenes, vanillins, camphors, azines, musks, ketones, acids, benzenes, lactones, and sulfides. The BT olfactory receptor in this specification is an olfactory receptor that responds to preferably 38% or more groups, more preferably 77% or more groups, when the response to preferably 9 or more groups, more preferably 11 or more groups, and even more preferably 13 or more groups of the above structural classes is examined. In addition, the phrase "responds to a certain structural classification group (e.g., alcohols)" in relation to an olfactory receptor means that the olfactory receptor responds to at least one odorant, preferably three or more odorants, and more preferably four or more odorants that belong to that structural classification group.

The responsiveness of the olfactory receptor can be evaluated by comparing the response of the olfactory receptor (test group) to which the odorant has been added with that of a control group. Examples of the control group include the olfactory receptor to which a lower concentration of the odorant has been added, the olfactory receptor to which the odorant has not been added, the olfactory receptor to which a control substance has been added, the olfactory receptor before the odorant has been added, and cells in which the olfactory receptor is not expressed. If the response in the test group is enhanced compared to the control group, the olfactory receptor is determined to have responded to the odorant. For example, if the response in the test group is enhanced by preferably 120% or more, more preferably 150% or more, and even more preferably 200% or more compared to the control group, the olfactory receptor is determined to have responded to the odorant. Alternatively, if the response in the test group is statistically significantly enhanced compared to the control group, the olfactory receptor is determined to have responded to the odorant.

On the other hand, the inhibitory effect of the test substance on the olfactory receptor can be evaluated by comparing the response of the olfactory receptor (test group) to which the odorant to which the olfactory receptor responds and the test substance have been added with that of the control group. Examples of the control group include the olfactory receptor to which the odorant to which the olfactory receptor responds and a lower concentration of the test substance have been added, the olfactory receptor to which the odorant to which the olfactory receptor responds has been added but the test substance has not been added, and the olfactory receptor to which the odorant to which the olfactory receptor responds and a control substance have been added. If the response in the test group is more inhibited than in the control group, the test substance is determined to have inhibited the olfactory receptor. For example, if the response in the test group is inhibited by preferably 90% or less, more preferably 70% or less, and even more preferably 50% or less compared to the control group, the test substance is determined to have inhibited the olfactory receptor. Alternatively, if the response in the test group is inhibited statistically significantly compared to the control group, the test substance is determined to have inhibited the olfactory receptor.

In this specification, OR2W1 refers to the human olfactory receptor OR2W1 (olfactory receptor family 2 subfamily W member 1). Information on the nucleotide sequence and amino acid sequence of OR2W1 is registered in Genbank ([www.ncbi.nlm.nih.gov/genbank/]) (GeneID: 26692, protein_id: NP_112165.1). OR2W1 is a BT receptor that responds to alcohols, aldehydes, esters, ketones, acids, terpenes, vanillins, benzenes, and lactones (Patent Document 2).

The inventor's research group previously constructed a BT receptor single response model that selectively activates only the BT receptor OR2W1, and verified the role of the BT receptor. More specifically, they found that the amino acid l-arginine is a substance that activates only OR2W1 among human olfactory receptors. Subjects who received l-arginine and a fragrance simultaneously in their nasal cavities had an enhanced sense of smell for the fragrance. This enhanced sense of smell by l-arginine occurred not only for fragrances that activate OR2W1, but also for fragrances that do not activate OR2W1. However, when only l-arginine was applied to the nasal cavities, the subjects did not experience any sense of smell. These results showed that activation of OR2W1 is not involved in the generation of odor quality (specific odor), but transmits information on odor intensity (Patent Document 2).

From the above research, it has been found that BT receptors contribute to controlling the intensity of the smell sensation for various odorants, including those to which they themselves are responsive and those to which they are not. Patent Document 2 provides a method for using a substance that controls the response of BT receptors as a substance that controls the smell sensation regardless of the type of odor, and for selecting a substance that causes an enhancement or suppression of the smell sensation regardless of the type of odor based on the response of BT receptors.

Based on the above findings, the present inventors have now discovered substances that suppress the response of the BT receptor OR2W1 (i.e., inhibit OR2W1) and identified them as substances that can suppress the sense of smell regardless of the type of odor. In the following description of this specification, the substances identified in this invention that can suppress the sense of smell regardless of the type of odor may be referred to as broadly tuned (BT) odor sense suppressants, after the olfactory receptors used in their discovery.

The BT odor sense suppressing agents provided by the present invention include the following substances.
Ambrette Ride: CAS 7779-50-2
Muscon: CAS 541-91-3
Damascenone: CAS 23696-85-7
All of the above substances can be purchased commercially. For example, they can be obtained from Sigma-Aldrich, MP biomedical, etc. Alternatively, the same substances as the commercially available products or compositions containing them can be produced by chemical synthesis.

As shown in the examples below, the above-mentioned BT odor sense suppressant suppressed the response of the BT receptor OR2W1 (i.e., inhibited OR2W1). Therefore, it is considered that the BT odor sense suppressant can suppress the odor sense for various odors regardless of the type of odor through such an inhibitory action of OR2W1. On the other hand, the substance whose odor sense is suppressed by the BT odor sense suppressant may be a substance that activates OR2W1 or a substance that does not have an OR2W1 activating action. For example, the BT odor sense suppressant according to the present invention can suppress the odor sense of compounds belonging to alcohols, aldehydes, esters, ketones, acids, terpenes, vanillins, benzenes, and lactones, which are odor substances that activate OR2W1, as well as compounds belonging to any odor substance, such as compounds belonging to each group classified according to the structural classification of odor substances (see Non-Patent Document 1), namely, amines, thiols, alcohols, esters, ethers, aldehydes, cyclic alkanes, terpenes, vanillins, camphors, azines, musks, ketones, acids, benzenes, lactones, and sulfides.

The present invention relates to the BT odor sense suppressant described above, and its use for odor suppression. By using the BT odor sense suppressant, it is possible to suppress the odor sense for various odors, regardless of the type of odor. Thus, in one aspect, the present invention provides an odor sense suppressant containing at least one active ingredient selected from the group consisting of ambrettolide, muscone, and damascenone. The odor sense suppressant of the present invention is capable of suppressing the odor sense for various odors, regardless of the type of odor.

In one embodiment, the odor sense suppressant of the present invention may essentially consist of at least one selected from the group consisting of ambrettolide, muscone, and damascenone. In another embodiment, the odor sense suppressant of the present invention is a composition containing at least one selected from the group consisting of ambrettolide, muscone, and damascenone as an active ingredient for odor sense suppression.

In another aspect, the present invention provides the use of at least one selected from the group consisting of ambrettolide, muscone, and damascenone in the manufacture of an odor sense suppressant. In another aspect, the present invention provides the use of at least one selected from the group consisting of ambrettolide, muscone, and damascenone for odor sense suppression. In another aspect, the present invention provides a method for odor sense suppression, comprising applying to a subject an effective amount of at least one selected from the group consisting of ambrettolide, muscone, and damascenone. The odor sense suppression according to the present invention can suppress the odor sense for various odors regardless of the type of odor.

The type of target odor whose sense of smell is suppressed by the present invention is not particularly limited, but may be, for example, the odor of at least one compound selected from the group consisting of amines, thiols, alcohols, esters, ethers, aldehydes, cyclic alkanes, terpenes, vanillins, camphors, azines, musks, ketones, acids, benzenes, lactones, and sulfides, preferably the odor of at least one compound selected from the group consisting of compounds belonging to alcohols, aldehydes, esters, azines, ketones, acids, terpenes, vanillins, benzenes, and lactones, and more preferably the odor of at least one compound selected from the group consisting of compounds belonging to alcohols, azines, aldehydes, and acids. More specific examples of target odors include the odors of commonly used fragrances (e.g., animal-based fragrances such as musk, civet, castoreum, and ambergris; plant-derived essential oils; plant-based fragrances such as rose, jasmine, neroli, lavender, clove, peppermint, sandalwood, cinnamon, lemon, orange, and bergamot, or extracts thereof (e.g., phenylethyl alcohol); the odors of food or its ingredients; and the odors of other odorous substances (e.g., cosmetics, medicines, cleaning agents, daily necessities, etc.); and the odors of malodorous substances (e.g., gas fragrances, hydrogen sulfide, chlorine gas, putrid odors, toilet odors, body odors, bad breath, armpit odors, sweat odors, tobacco odors, indole odors, skatole odors, pyridine odors, pyrazine odors, etc.).

In the present invention, subjects to which the BT odor sense suppressant is applied include mammals that desire or require the suppression of the odor sense for the target odors described above. The types of mammals are not limited, but include, for example, primates such as humans, chimpanzees, and monkeys, and rodents such as mice and rats, preferably humans, mice, and rats, and more preferably humans. Examples of people who desire or require the suppression of the odor sense include, for example, people who work in the presence of foul odors (e.g., people involved in cleaning and garbage collection); people who live in places where there are multiple different odors such as cooking odors, drain odors, mold odors, garbage odors, and body odors, and who wish to suppress these multiple odors (e.g., people living in a living room at home); people who wish to suppress the body odor of people around them or the overly strong odor of perfumes; people who experience environments where they are exposed to various odors from the surroundings, such as environments where many people are crowded together in a small space (e.g., crowded public transportation); people with hyperosmia, etc., who wish to reduce the discomfort caused by odors.

One embodiment of the use of the BT odor sense suppressant in the present invention is as follows: First, the BT odor sense suppressant is applied to a subject who desires or requires suppression of a target odor sense before or together with exposure to the target odor. This inhibits OR2W1 on the olfactory epithelium, causing the subject's odor sense to be suppressed for the target odor. As a result, even if the subject is exposed to the target odor, the target odor is not sensed or is sensed less strongly (or detected at a higher detection threshold).

The method of applying the BT odor sense suppressant to a subject may be any method that allows the agent to reach the olfactory cells of the subject. Examples include a method of volatilizing the BT odor sense suppressant from a composition containing the BT odor sense suppressant and having the subject inhale it, a method of atomizing a liquid containing the BT odor sense suppressant and spraying it to have the subject inhale it, a method of spraying or instilling a liquid containing the BT odor sense suppressant into the nasal cavity, a method of applying a liquid, gel, cream, ointment, etc. containing the BT odor sense suppressant into the nasal cavity, a method of placing a solid carrier (e.g., cotton ball, etc.) containing the BT odor sense suppressant into the nasal cavity, etc.

The effective amount of the BT odor sense suppressant used in the present invention is not particularly limited, as long as it is an amount capable of inhibiting OR2W1 in the nasal cavity of the subject, or a range capable of suppressing the subject's odor sense. The effective amount can be appropriately adjusted according to the species, age, and natural odor sense sensitivity of the subject, the method of application of the agent, the intensity and sensitivity of the target odor whose odor sense is to be suppressed, and the subject's surrounding environment. However, it is preferable that the odor of the BT odor sense suppressant itself is not too strong compared to the target odor. For example, it is preferable that the BT odor sense suppressant is used at a concentration lower than the concentration of the target odor, or at a concentration below the odor detection threshold of the BT odor sense suppressant in the subject.

For example, when the BT odor sense suppressant is inhaled by a subject, the concentration of the BT odor sense suppressant in the nasal cavity of the subject has a lower limit of preferably 12.0 μg/L air, more preferably 1.2 μg/L air, even more preferably 0.12 μg/L air, even more preferably 0.04 μg/L air, and even more preferably 0.012 μg/L air, while the upper limit is preferably 1000 μg/L air, more preferably 100 μg/L air, and even more preferably 30 μg/L air. Alternatively, the concentration of the BT odor sense suppressant in the nasal cavity of the subject is preferably 12.0 to 1000 μg/L air, 12.0 to 100 μg/L air, or 12.0 to 30 μg/L air, more preferably 1.2 to 1000 μg/L air, 1.2 to 100 μg/L air, or 1.2 to 30 μg/L air, even more preferably 0.12 to 1000 μg/L air, 0.12 to 100 μg/L air, or 0.12 to 30 μg/L air, and even more preferably 0.04 to 1000 μg/L air, 0.04 to 100 μg/L air, or 0.04 to 30 μg/L air. air, and more preferably 0.012 to 1000 μg/L air, 0.012 to 100 μg/L air, or 0.012 to 30 μg/L air.

For example, when the BT odor sense suppressant is volatilized from a composition containing the BT odor sense suppressant and inhaled by a subject, the concentration of the BT odor sense suppressant in the composition has a lower limit of preferably 300 μM, more preferably 30 μM, and even more preferably 3 μM, while the upper limit is preferably 300,000 μM, more preferably 30,000 μM, and even more preferably 10,000 μM. Alternatively, the concentration of the BT odor sense suppressant in the composition is preferably 300 to 300,000 μM, 300 to 30,000 μM, or 300 to 10,000 μM, more preferably 30 to 300,000 μM, 30 to 30,000 μM, or 30 to 10,000 μM, and even more preferably 3 to 300,000 μM, 3 to 30,000 μM, or 3 to 10,000 μM.

Examples of applications of the BT odor sense suppressant according to the present invention include use in spaces where odor suppression is desired, such as toilets, bathrooms, hospital wards or nursing facilities, or residences including kitchens, bedrooms, closets, etc. (e.g., spaces where multiple different odors such as body odor, damp odor, moldy odor, etc. occur); use in environments where a large number of people are crowded together in a small space and may be exposed to various odors such as body odor and fragrances from the people around them (e.g., crowded public transportation); addition to products intended to suppress odor (e.g., deodorants, topical deodorants, or deodorant cleaning agents, laundry detergents or fabric softeners); addition to products intended to suppress odor (e.g., disposable diapers, sanitary products, underwear, undergarments, linens, masks, or other clothing accessories, cloth products or textiles, medicines, foods, etc.); use in production lines of products having a target odor or environments generating a target odor for the purpose of suppressing odor, etc. However, application examples of the BT odor sense suppressant are not limited to these.

As exemplary embodiments of the present invention, the following compositions, manufacturing methods, uses or methods are further disclosed in this specification. However, the present invention is not limited to these embodiments.

[1] An odor sense suppressant that contains at least one active ingredient selected from the group consisting of ambrettolide, muscone, and damascenone, and that suppresses the odor sense regardless of the type of odor.
[2] The agent according to [1], which suppresses the sense of smell, preferably by inhibiting OR2W1.
[3] Preferably, the composition can suppress the odor sense of at least one compound selected from the group consisting of alcohols, azines, aldehydes, and acids;
More preferably, the odor sense for the odors of compounds belonging to alcohols, aldehydes, esters, azines, ketones, acids, terpenes, vanillins, benzenes, and lactones can be suppressed;
More preferably, the odor sense of compounds belonging to the following groups can be suppressed: amines, thiols, alcohols, esters, ethers, aldehydes, cyclic alkanes, terpenes, vanillins, camphors, azines, musks, ketones, acids, benzenes, lactones, and sulfides.
The agent described in [1] or [2].
[4] An OR2W1 inhibitor comprising at least one active ingredient selected from the group consisting of ambrettolide, muscone, and damascenone.
[5] The agent according to any one of [1] to [4], wherein the active ingredient is used at a concentration below the detection threshold of its own odor.
[6] Preferably, the composition volatilizes at least one selected from the group consisting of ambrettolide, muscone, and damascenone, and the total concentration of at least one selected from the group consisting of ambrettolide, muscone, and damascenone in the composition is as follows:
The lower limit is preferably 300 μM, more preferably 30 μM, and even more preferably 3 μM, and the upper limit is preferably 300,000 μM, more preferably 30,000 μM, and even more preferably 10,000 μM, or
The agent according to any one of [1] to [4], wherein the concentration is preferably 300 to 300,000 μM, 300 to 30,000 μM, 300 to 10,000 μM, 30 to 300,000 μM, 30 to 30,000 μM, 30 to 10,000 μM, 3 to 300,000 μM, 3 to 30,000 μM, or 3 to 10,000 μM.
[7] The total concentration of at least one selected from the group consisting of ambrettolide, muscone, and damascenone in the nasal cavity of a subject is used so as to be as follows:
The lower limit is preferably 12.0 μg/L air, more preferably 1.2 μg/L air, even more preferably 0.12 μg/L air, even more preferably 0.04 μg/L air, and even more preferably 0.012 μg/L air, and the upper limit is preferably 1000 μg/L air, more preferably 100 μg/L air, even more preferably 30 μg/L air, or preferably 12.0 to 1000 μg/L air, 12.0 to 100 μg/L air, 12.0 to 30 μg/L air, 1.2 to 1000 μg/L air, 1.2 to 100 μg/L air, 1.2 to 30 μg/L air, 0.12 to 1000 μg/L air, 0.12-100μg/L air, 0.12-30μg/L air, 0.04-1000μg/L air, 0.04-100μg/L air, 0.04-30μg/L air, 0.012-1000μg/L air, 0.012 to 100 μg/L air, or 0.012 to 30 μg/L air,
The agent according to any one of [1] to [4].

[8] Use of at least one member selected from the group consisting of ambrettolide, muscone, and damascenone in the manufacture of an odor sense suppressant that suppresses odor sense regardless of the type of odor.
[9] Use of at least one member selected from the group consisting of ambrettolide, muscone, and damascenone to suppress the sense of smell regardless of the type of odor.
[10] The use according to [8] or [9], wherein the odor sense inhibition is preferably achieved by inhibiting OR2W1.
[11] The odor sense suppression,
Preferably, it enables the suppression of the smell sensation due to at least one compound selected from the group consisting of compounds belonging to the alcohols, azines, aldehydes and acids,
More preferably, it enables the suppression of the smell sensation due to the smell of compounds belonging to the following classes: alcohols, aldehydes, esters, azines, ketones, acids, terpenes, vanillins, benzenes and lactones;
More preferably, it enables the inhibition of the smell sensation due to the smell of compounds belonging to the following classes: amines, thiols, alcohols, esters, ethers, aldehydes, cyclic alkanes, terpenes, vanillins, camphors, azines, musks, ketones, acids, benzenes, lactones, and sulfides.
The use according to any one of [8] to [10].
[12] Use of at least one selected from the group consisting of ambrettolide, muscone, and damascenone in the manufacture of an OR2W1 inhibitor.
[13] Use of at least one selected from the group consisting of ambrettolide, muscone, and damascenone for inhibiting OR2W1.
[14] The use according to any one of [8] to [13], wherein at least one selected from the group consisting of ambrettolide, muscone, and damascenone is used at a concentration below its own odor detection threshold.
[15] Preferably, the agent is a composition that volatilizes at least one selected from the group consisting of ambrettolide, muscone, and damascenone, or at least one selected from the group consisting of ambrettolide, muscone, and damascenone is volatilized from a composition containing it, and the total concentration of at least one selected from the group consisting of ambrettolide, muscone, and damascenone in the composition is as follows:
The lower limit is preferably 300 μM, more preferably 30 μM, and even more preferably 3 μM, and the upper limit is preferably 300,000 μM, more preferably 30,000 μM, and even more preferably 10,000 μM, or
Preferably, it is 300 to 300,000 μM, 300 to 30,000 μM, or 300 to 10,000 μM, 30 to 300,000 μM, 30 to 30,000 μM, 30 to 10,000 μM, 3 to 300,000 μM, 3 to 30,000 μM, or 3 to 10,000 μM.
The use according to any one of [8] to [13].
[16] The agent or at least one selected from the group consisting of ambrettolide, muscone, and damascenone is used so that the total concentration of at least one selected from the group consisting of ambrettolide, muscone, and damascenone in the nasal cavity of a subject is as follows:
The lower limit is preferably 12.0 μg/L air, more preferably 1.2 μg/L air, even more preferably 0.12 μg/L air, even more preferably 0.04 μg/L air, and even more preferably 0.012 μg/L air, and the upper limit is preferably 1000 μg/L air, more preferably 100 μg/L air, even more preferably 30 μg/L air, or preferably 12.0 to 1000 μg/L air, 12.0 to 100 μg/L air, 12.0 to 30 μg/L air, 1.2 to 1000 μg/L air, 1.2 to 100 μg/L air, 1.2 to 30 μg/L air, 0.12 to 1000 μg/L air, 0.12-100μg/L air, 0.12-30μg/L air, 0.04-1000μg/L air, 0.04-100μg/L air, 0.04-30μg/L air, 0.012-1000μg/L air, 0.012 to 100 μg/L air, or 0.012 to 30 μg/L air,
The use according to any one of [8] to [13].

[17] A method for suppressing odor sense regardless of the type of odor, comprising applying an effective amount of at least one selected from the group consisting of ambrettolide, muscone, and damascenone to a subject in need thereof.
[18] The method according to [17], wherein the application preferably inhibits OR2W1.
[19] The method further comprises:
Preferably, it makes it possible to suppress the smell sensation due to at least one compound selected from the group consisting of compounds belonging to alcohols, azines, and acids,
More preferably, it makes it possible to suppress the smell sensation due to the smell of compounds belonging to alcohols, aldehydes, esters, azines, ketones, acids, terpenes, vanillins, benzenes and lactones,
More preferably, it makes it possible to suppress the smell sensation due to the smell of compounds belonging to the following classes: amines, thiols, alcohols, esters, ethers, aldehydes, cyclic alkanes, terpenes, vanillins, camphors, azines, musks, ketones, acids, benzenes, lactones, and sulfides.
The method described in [17] or [18].
[20] A method for inhibiting OR2W1, comprising administering an effective amount of at least one selected from the group consisting of ambrettolide, muscone, and damascenone to a subject in need thereof.
[21] The method according to any one of [17] to [20], wherein at least one selected from the group consisting of ambrettolide, muscone, and damascenone is applied at a concentration below its own odor detection threshold.
[22] Preferably, the method includes having the subject inhale at least one selected from the group consisting of ambrettolide, muscone, and damascenone volatilized from the composition, and the total concentration of at least one selected from the group consisting of ambrettolide, muscone, and damascenone in the composition is as follows:
The lower limit is preferably 300 μM, more preferably 30 μM, and even more preferably 3 μM, and the upper limit is preferably 300,000 μM, more preferably 30,000 μM, and even more preferably 10,000 μM, or
Preferably, it is 300 to 300,000 μM, 300 to 30,000 μM, or 300 to 10,000 μM, 30 to 300,000 μM, 30 to 30,000 μM, 30 to 10,000 μM, 3 to 300,000 μM, 3 to 30,000 μM, or 3 to 10,000 μM.
The method according to any one of [17] to [20].
[23] The effective amount, as a total concentration of at least one selected from the group consisting of ambrettolide, muscone, and damascenone in the nasal cavity of the subject, is as follows: a lower limit of preferably 12.0 μg/L air, more preferably 1.2 μg/L air, even more preferably 0.12 μg/L air, even more preferably 0.04 μg/L air, even more preferably 0.012 μg/L air, and an upper limit of preferably 1000 μg/L air, more preferably 100 μg/L air, even more preferably 30 μg/L air, or preferably 12.0 to 1000 μg/L air, 12.0 to 100 μg/L air, 12.0 to 30 μg/L air, 1.2 to 1000 μg/L air. air, 1.2-100μg/L air, 1.2-30μg/L air, 0.12-1000μg/L air, 0.12-100μg/L air, 0.12-30μg/L air, 0.04-1000μg/L air, 0.04-100μg/L air, 0.04 to 30 μg/L air, 0.012 to 1000 μg/L air, 0.012 to 100 μg/L air, or 0.012 to 30 μg/L air,
The method according to any one of [17] to [20].

The following examples will explain the present invention in more detail.

Example 1 Inhibitory effect of test substance on broadly tuned olfactory receptor OR2W1 1) Test substance: ambrettolide (Sigma-Aldrich)
Muscone: (MP biomedical)
Damascenone (Sigma-Aldrich)

2) Cloning of OR2W1 Based on the sequence information registered in GenBank, the gene encoding the human olfactory receptor OR2W1 was cloned. The OR2W1 gene was cloned by PCR using human genomic DNA female (G1521: Promega) as a template. The OR2W1 gene amplified by PCR was recombined downstream of the Flag-Rho tag sequence on the pME18S vector.

3) Preparation of pME18S-human RTP1S vector The gene encoding human RTP1S was cloned by PCR using human genomic DNA female (G1521: Promega) as a template. The obtained human RTP1S gene was inserted into the EcoRI and XhoI sites of the pME18S vector.

4) Preparation of Olfactory Receptor-Expressing Cells HEK293 cells expressing OR2W1 were prepared. A reaction solution having the composition shown in Table 1 was prepared and left to stand in a clean bench for 15 minutes. 10 μL of the reaction solution was added to each well of a multi-well plate (96-well plate, BioCoat), followed by addition of 90 μL of a HEK293 cell suspension (3×10 ⁵ cells/cm ² ). The cells were cultured for 24 hours in an incubator maintained at 37° C. and 5% CO ₂ .

5) Luciferase Assay The olfactory receptor expressed in HEK293 cells increases the amount of intracellular cAMP by coupling with the intrinsic Gαs and activating adenylate cyclase. In this embodiment, a luciferase reporter gene assay was used to monitor the increase in intracellular cAMP as a luminescence value derived from the firefly luciferase gene (fluc2P-CRE-hygro) for cell response measurement. In addition, a Renilla luciferase gene fused downstream of the CMV promoter (hRluc-CMV) was simultaneously transfected into the cells and used as an internal standard to correct errors in transfection efficiency or cell number. The medium was removed from the cell culture prepared in 4), and 75 μL of HBSS (GIBCO) solution containing the test substance (final concentration 100 μM) and hexanol (final concentration 10 μM), a known agonist of OR2W1, was added to each well (test group). As a control group, an equal amount of HBSS solution containing hexanol at a final concentration of 10 μM was added to the wells. As a reference (Buffer group), an equal amount of HBSS solution alone was added to the wells. The cells were cultured in a _CO2 incubator for 4 hours to fully express the luciferase gene in the cells. The luciferase activity derived from the cells was measured 4 hours after stimulation with the test substance using a Dual-Glo ^™ luciferase assay system (Promega) according to the product's operating manual. The value fLuc/hRluc obtained by dividing the luminescence value fLuc derived from firefly luciferase by the luminescence value hRluc derived from Renilla luciferase was calculated and used as an index of the cell response. The response inhibition level of OR2W1 by the test substance was calculated according to the following formula.
Response inhibition level = X/Y
X: (fLuc/hRluc in the test group) - (fLuc/hRluc in the buffer group)
Y: (fLuc/hRluc in the control group)-(fLuc/hRluc in the buffer group)

6) Results The OR2W1 inhibitory activity of the test substances is shown in Figure 1. Compared to the control group, ambrettolide, muscone, and damascenone all suppressed the hexanol response of OR2W1. This result demonstrated that ambrettolide, muscone, and damascenone are OR2W1 inhibitors.

Example 2 Odor suppression effect of test substances 1) Suppression of indole odor by ambrettolide, muscone and damascenone The suppression effect of the test substances on malodor (indole odor) was evaluated. Mineral oil solutions containing each test substance or indole at a concentration of 10 mM were prepared. 5 μL of either the test substance solution, the indole solution or mineral oil was soaked into a cotton ball and placed in a 20 mL vial. A vial containing a cotton ball containing the test substance solution and a cotton ball containing the indole solution (test sample), a vial containing a cotton ball containing mineral oil and a cotton ball containing the indole solution (blank), and a vial containing only a cotton ball containing the indole solution (control sample) were prepared.

Four expert panelists were asked to smell the control sample and the test sample or blank alternately, and to answer what percentage of the indole odor they perceived in the test sample and blank compared to the control sample. All odor evaluations were done blind, and the order in which each test sample and blank was evaluated was random. The results of the odor evaluation are shown in Figure 2. Due to the adaptation effect, the odor of the blank was perceived as weaker than that of the control sample. Test substances that were answered to have an odor even weaker than that of the blank were considered to have an odor-suppressing effect. Ambrettolide, muscone, and damascenone all suppressed the odor of indole.

2) Inhibition of phenylethyl alcohol (PEA) odor by ambrettolide, muscone and damascenone The inhibitory effect of the test substance on the odor (rose-like odor due to PEA) was evaluated. Mineral oil solutions containing each test substance or PEA at a concentration of 10 mM were prepared. 20 μL of either the test substance solution, the PEA solution or mineral oil was soaked into a cotton ball and placed in a 20 mL vial. A vial containing a cotton ball containing the test substance solution and a cotton ball containing the PEA solution (test sample), a vial containing a cotton ball containing mineral oil and a cotton ball containing the PEA solution (blank), and a vial containing only a cotton ball containing the PEA solution (control sample) were prepared.

Three expert panelists were asked to alternately smell the control sample and the test sample or blank, and to evaluate the degree to which the PEA odor of the test sample and blank was perceived compared to the control sample using a visual analogue scale (VAS). In the VAS evaluation, the left end of a 10 cm line was marked "0 cm: not felt at all" and the right end was marked "10 cm: felt very strongly", and the evaluators were asked to indicate where on the line the PEA odor of each sample fell. The distance (mm) from 0 cm to the marked position was taken as the VAS measurement value. All odor evaluations were performed blind, and the order in which each test sample and blank were evaluated was random. The results are shown in Figure 3. Test substances that were rated as having a weaker odor than the blank were considered to have an odor suppressing effect. Ambrettolide, muscone, and damascenone all suppressed the PEA odor.

3) Suppression of various odors by low concentration ambrettolide The suppression effect of various malodors by ambrettolide solution (0.01 w/v% dipropylene glycol dilution solution) at a concentration below the detection threshold was examined. Malodor solution was dropped onto a 9 cm square knitted cotton cloth placed in a petri dish, and 50 μL of ambrettolide solution was dropped around it so as not to overlap with the drop of the malodor solution (test cloth). A control cloth without ambrettolide was prepared using the same procedure. The malodor solution was prepared as follows, and used so that the odor when dropped onto the cloth was easily noticeable. In the evaluation of the odor suppression effect, a panel of 6 to 7 experts evaluated the malodor of the test cloth by pairwise comparison between the control cloth and the test cloth, using the malodor of the control cloth as the standard. The odor of the test fabric was evaluated on a five-point scale: "The odor of the control fabric is stronger,""The odor of the control fabric is somewhat stronger,""Can'tsay,""The odor of the test fabric is somewhat stronger," and "The odor of the test fabric is stronger."
<Foul-smelling solution>
Skatole 1000 ppm solution (solvent: acetone) 5 μL
Isovaleric acid 1000 ppm solution (solvent: water) 1 μL
Model tobacco odor solution 1 μL

The results of the evaluation by the expert panel (n=6-7) are shown in Figure 4. The number of people who selected each malodor level is shown in the table in Figure 4. For each malodor, more than two-thirds of the expert panel rated the test fabric (with ambrettolide) as having a lower malodor intensity than the control fabric (without ambrettolide). This demonstrates that ambrettolide suppresses various odors even at low concentrations below the detection threshold.

The results of the above examples suggest that ambrettolide, muscone, and damascenone have the effect of suppressing odors regardless of the type of odor, that this odor-suppressing effect is presumed to be mediated by the inhibition of OR2W1, and that the odor-suppressing effect of these substances is exerted even at concentrations below the detection threshold of their own odors, suggesting that this occurs through a mechanism different from the malodor masking caused by the substances' own odors.

Claims (1)

An OR2W1 inhibitor whose active ingredient is ambrettolide.