JP2022047344A - Agent for suppressing sense of smell - Google Patents

Abstract

To provide an agent for suppressing a sense of smell to various smells.SOLUTION: An agent for suppressing a sense of smell contains at least one selected from the group consisting of ambrettolide, muscone, and damascenone as an active ingredient. The agent suppresses a sense of smell regardless of the type of the smell.SELECTED DRAWING: None

Description

The present invention relates to an odor suppressant.

Smell plays an important role in enriching daily life. For example, the scent of food provides a rich flavor, and the scent of daily products provides various pleasures such as cleanliness. On the other hand, unpleasant odors are also important. Smell plays a major role in promptly informing that health and hygiene are impaired. However, there are many people who are uncomfortable with the smell of perfumes and fabric softeners worn by others. In addition, cases of hyperosmia due to illness and stress have been reported, and these patients are stressed on a daily basis because they strongly feel all odors, and in severe cases, they may interfere with their lives. ..

Most of the odorants are volatile low molecular weight organic compounds with a molecular weight of about 30-300. These odorants vary in their chemical structure as well as their odor quality, and are often classified based on their chemical structure in studies from a molecular biological point of view. For example, in Non-Patent Document 1, 125 kinds of odorants are referred to as amines, thiols, alcohols, esters, ethers, aldehydes, cyclic alkanes, terpenes, vanillins, camphors, azines, and musk. Classes, as well as ketones and others, are classified into 13 groups. Further, in Patent Document 1, odorants are classified into nine categories: amines, alcohols, aldehydes, ketones, acids, esters, benzenes, vanillin-like compounds, and lactones.

The odorant is recognized by the olfactory receptors of the olfactory nerve cells that spread to the deepest part of the nasal cavity. Olfactory receptors bind and activate odorants, causing electrical excitement in olfactory nerve cells. Smell is perceived by transmitting this electrical excitement to the higher brain via neural connections. There are about 400 types of genes encoding the olfactory receptor in humans. This large number of receptors is the molecular basis that enables the detection of the various odors described above. Each of these approximately 400 types of olfactory receptors is expressed in different olfactory nerve cells. On the other hand, olfactory nerve cells expressing the same olfactory receptor converge to the same region peculiar to the projection destination of axons in the olfactory bulb. Therefore, the information on which olfactory receptor is activated in the nasal cavity is reflected in the geometric information of the region of the olfactory bulb that ignites, and is transmitted to the higher brain region without loss. In this way, it is thought that information on the combination of olfactory receptors that are activated for individual odorants is transmitted to the higher brain regions, causing differences in odor quality.

Knowledge has been accumulated regarding the relationship between odor and the olfactory receptors involved in its recognition. According to them, the olfactory receptors generally selectively recognize structurally similar odorants. For example, Non-Patent Document 1 suggests that about 45% of about 1,000 olfactory receptors in mice recognize only one group of odorants chemically structurally classified into 13 groups. ing. On the other hand, in Non-Patent Document 1, 13.4% of olfactory receptors recognize 5 to 9 groups of odorants, and 1.8% of them are structurally extremely wide-ranging odorants of 10 to 12 groups. It is suggested to recognize. The olfactory receptor that recognizes such a wide range of odorants is called the Bloody Tuned olfactory receptor. As a typical Broadly Tuned olfactory receptor, Mouse Olfr42 is mentioned in Non-Patent Document 1. OR2W1, which is a human homologous gene of Olfr42, is also listed as a Broadly Tuned olfactory receptor by Non-Patent Document 2. Conventionally, a plurality of hypotheses have been proposed regarding the role of the Broadly Tuned olfactory receptor (Non-Patent Document 2), and these hypotheses have not been verified.

Recently, a BT receptor-only 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 validated. Patent Document 2 reports that by enhancing the activity of the BT receptor, the odor of various odorous substances can be felt more sensitively or more strongly, and the BT receptor can be used for various odorous substances. It is suggested that it conveys information on the strength of the odor rather than the quality of the odor. Further, Patent Document 2 describes that a substance that controls the response of a BT receptor can be used as a substance that controls an odor sensation 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 odor sensation. The present invention relates to an odor sensation inhibitor capable of suppressing an odor sensation regardless of the type of odor.

The present inventor has found a substance that inhibits the Bloody Tuned olfactory receptor OR2W1. These substances can suppress the odor sensation for various odor substances regardless of the type of odor through the inhibition of OR2W1.

Therefore, the present invention provides an odor sensation inhibitor that suppresses an odor sensation regardless of the type of odor, which comprises at least one selected from the group consisting of ambrette ride, muscone, and damascenone as an active ingredient.

The odor sensation inhibitor of the present invention can suppress the odor sensation for various odors regardless of the type of odor by inhibiting the Broadly Tuned olfactory receptor OR2W1.

OR2W1 inhibitory activity by Amblet Ride, Muscone and Damascenone. The data represent the mean and standard error of the response suppression level of OR2W1 from 3 experiments. When the value of the response suppression level is smaller than 1, it indicates an inhibition tendency, and when the value of the response suppression level is smaller, it indicates that the inhibition is stronger. Indole odor suppression effect by Amblet Ride, Muscone, and Damascenone. The data is the average value of the evaluation by the panel of four people, and the error bar is the standard error. PEA scent suppression effect by Amblet Ride, Muscone, Damascenone. The data is the average value of the evaluation by the panel of three people, and the error bar is the standard error. Amblet ride below the detection threshold has the effect of suppressing various odors. Six to seven specialized panels evaluated the malodor of the test cloth on a five-point scale by pairwise comparison between the control cloth (smell only, no ambrette ride) and the test cloth (sink + ambrette ride). The number of people who selected each stink stage is shown in the table.

As used herein, the term "suppression of odor sensation" refers to a phenomenon in which an individual's sensitivity to odor decreases. The strength of sensitivity to odor can be evaluated based on the detection intensity or detection threshold value (sensitivity) to odor. For example, when the detection intensity for the target's odor decreases or the detection threshold increases (or the detection sensitivity decreases), it is determined that the target's sensitivity to the odor has decreased, and at this time, the odor sensation of the target's odor is suppressed. Has been done.

In the present specification, the "substance that causes suppression of odor sensation" (so-called odor suppressant) means the target when the substance is used in combination with the target odor substance (for example, used at the same time as or in advance of the target odor substance). It is a substance that causes a subject to feel a weak odor or detect it with low sensitivity (at a high concentration threshold) as compared with the case where an odor substance is applied alone. The substance that causes the suppression of odor sensation may have an odor in itself.

As used herein, "Broadly Tuned olfactory receptors" (also referred to herein as "BT receptors") have different odors, unlike many olfactory receptors that selectively recognize a small number of specific odorants. It is an olfactory receptor that responds to multiple types of odorants. More specifically, a BT receptor refers to an olfactory receptor that responds to multiple odorants belonging to different structural classifications. Examples of structural classifications of odorants include amines, thiols, alcohols, esters, ethers, aldehydes, cyclic alkanes, terpenes, vanillins, camphors, azines, musks, and ketones. , Acids, benzenes, lactones, sulfides and the like. The BT olfactory receptor in the present specification is preferably 9 or more groups, more preferably 11 or more groups, still more preferably 13 or more groups among the above structural classifications when the response to them is examined. It is an olfactory receptor that responds to a group of 38% or more, more preferably 77% or more. In addition, regarding the olfactory receptor, "responding to a certain structural classification group (for example, alcohols)" means that the olfactory receptor belongs to at least one kind, preferably three or more kinds belonging to the structural classification group. , More preferably, it means responding to four or more odorants.

The responsiveness of the olfactory receptor can be evaluated by comparing the response of the olfactory receptor (test group) to which the odorant is added with that of the control group. As a control group, the olfactory receptor to which the odorant was added at a lower concentration, the olfactory receptor to which the odorant was not added, the olfactory receptor to which the control substance was added, and before the odorant was added. The olfactory receptor of the above, cells in which the olfactory receptor is not expressed, and the like can be mentioned. If the response in the test group is enhanced over that in 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 to preferably 120% or more, more preferably 150% or more, still more preferably 200% or more as compared with the control group, the olfactory receptor is the odorant. It is determined that the response has been made. Alternatively, if the response in the test group is statistically significantly enhanced as compared to the control group, the olfactory receptor is determined to have responded to the odorant.

On the other hand, the evaluation of the inhibitory effect of the test substance on the olfactory receptor is performed by comparing the response of the olfactory receptor (test group) to which the odorant substance to which the test substance responds and the test substance are added with the control group. be able to. As a control group, the olfactory receptor to which the olfactory receptor responds and the test substance having a lower concentration are added, and the test substance is added while the olfactory receptor responds to the olfactory receptor. Examples thereof include the olfactory receptor that did not respond, the olfactory receptor to which an odorant substance to which the olfactory receptor responds and a control substance are added, and the like. If the response in the test group is more suppressed than in the control group, it is determined that the test substance has suppressed the olfactory receptor. For example, if the response in the test group is preferably suppressed to 90% or less, more preferably 70% or less, still more preferably 50% or less as compared with the control group, the test substance suppresses the olfactory receptor. It is determined that it has been done. Alternatively, if the response in the test group is statistically significantly suppressed as compared with the control group, it is determined that the test substance has suppressed the olfactory receptor.

In the present specification, OR2W1 refers to human olfactory receptor family 2 subfamily W member 1 (olfactory receptor family 2 subfamily W member 1). Information on the nucleotide and amino acid sequences 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).

Previously, the research group of the present inventor constructed a BT receptor-only response model that selectively activates only the BT receptor OR2W1 and examined the role of the BT receptor. More specifically, it has been 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 into the nasal cavity had an enhanced odor sensation for the fragrance. This enhancement of the odor sensation by l-arginine occurred not only for the fragrance that activates OR2W1 but also for the fragrance that does not activate OR2W1. However, subjects did not develop a sensation of odor when only l-arginine was applied intranasally. From these results, it was shown that the activation of OR2W1 was not involved in the generation of odor quality (specific odor) and transmitted information on the intensity of odor (Patent Document 2).

From the above studies, it was found that the BT receptor contributes to the control of the intensity of odor sensation for various odorous substances, including substances that are responsive and those that are not. In Patent Document 2, a substance that controls the response of the BT receptor is used as a substance that controls the odor sensation regardless of the type of odor, and regardless of the type of odor based on the response of the BT receptor. A method of selecting a substance that causes an enhancement or suppression of odor sensation is provided.

Now, based on the above findings, the present inventor can find substances that suppress the response of the BT receptor OR2W1 (that is, inhibit OR2W1) and suppress the odor sensation of them regardless of the type of odor. Specified as a substance. In the following specification, the substance identified in the present invention capable of suppressing the odor sensation regardless of the type of the odor is classified as Bloody Tuned (BT), following the olfactory receptor used for the search thereof. Sometimes referred to as an odor suppressant.

Examples of the BT odor suppressant provided by the present invention include the following substances.
Amblet Ride: CAS 7779-50-2
Muscone: CAS 541-91-3
Damascenone: CAS 23696-85-7
All of the above substances can be purchased commercially. For example, it can be obtained from Sigma-Aldrich, MP biomedical, and the like. Alternatively, it is possible to produce the same substance as the commercially available product or a composition containing the same by chemical synthesis.

As shown in Examples described later, the above-mentioned BT odor suppressant suppressed the response of the BT receptor OR2W1 (that is, inhibited OR2W1). Therefore, it is considered that the BT odor suppressant can suppress the odor sensation for various odors regardless of the type of odor through the inhibitory action of OR2W1. On the other hand, the substance whose odor sensation is suppressed by the BT odor suppressant may be a substance that activates OR2W1 or a substance that does not have an OR2W1 activating action. For example, the BT odor suppressant according to the present invention is a compound belonging to alcohols, aldehydes, esters, ketones, acids, terpenes, vanillins, benzenes and lactones, which are odor substances that activate OR2W1. Not only can the odor sensation be suppressed, but also each group classified by structural classification of all odorous substances, for example, odorous substances (see Non-Patent Document 1), that is, amines, thiols, alcohols, esters, etc. Suppresses the odor of ethers, aldehydes, cyclic alcohols, terpenes, vanillins, camphors, azines, musks, ketones, acids, benzenes, lactones, and compounds belonging to sulfides. Can be a substance that can.

The present invention relates to the BT odor suppressants listed above and their use for odor control. By using the BT odor suppressant, it is possible to suppress the odor sensation for various odors regardless of the type of odor. Therefore, in one embodiment, the present invention provides an odor suppressant containing at least one selected from the group consisting of ambretteride, muscone, and damascenone as an active ingredient. The odor sensation inhibitor of the present invention can suppress odor sensations for various odors regardless of the type of odor.

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

In another aspect, the invention provides the use of at least one selected from the group consisting of ambretteride, muscone, and damascenone in the manufacture of odor suppressants. In another aspect, the invention provides the use of at least one selected from the group consisting of ambretteride, muscone, and damascenone for odor sensation suppression. In another embodiment, the present invention provides a method for suppressing odor sensation, which comprises applying an effective amount of at least one selected from the group consisting of ambrette ride, muscone, and damascenone to a subject. In the odor sensation suppression according to the present invention, it is possible to suppress odor sensations for various odors regardless of the type of odor.

The type of target odor in which the odor sensation is suppressed by the present invention is not particularly limited, but for example, amines, thiols, alcohols, esters, ethers, aldehydes, cyclic alkanes, terpenes, vanillins, etc. The odor of at least one compound selected from the group consisting of camphors, azines, musks, ketones, acids, benzenes, lactones, and sulfides, preferably alcohols, aldehydes, etc. It is the odor of at least one compound selected from the group consisting of compounds belonging to esters, azines, ketones, acids, terpenes, vanillins, benzenes and lactones, and more preferably alcohols and azines. The odor of at least one compound selected from the group consisting of compounds belonging to, aldehydes, and acids. More specific examples of target odors include commonly used fragrances (eg, animal fragrances such as musk, civet, castorium, amberglis; plant-derived essential oils; rose, jasmine, neroli, lavender, cloves, peppermint. , Sandalwood, cinnamon, lemon, orange, bergamot, or vegetable fragrances such as extracts thereof (eg phenylethyl alcohol); odors of foods or materials thereof; as well as other odorous substances (eg cosmetics) , Pharmaceuticals, cleaning agents, daily necessities, etc.; malodorous substances (eg, gas fragrances, hydrogen sulfide, chlorine gas, rotting odor, toilet odor, body odor, mouth odor, armpit odor, sweat odor, tobacco odor, indole odor , Scent of scatol, pyridine, pyrazine, etc.).

In the present invention, the subject to which the BT odor suppressant is applied includes mammals who desire or need to suppress the odor sensation to the target odor described above. The type of mammal is not limited, and examples thereof include primates such as humans, chimpanzees and monkeys, and rodents such as mice and rats, preferably humans, mice and rats, and more preferably. Humans are mentioned. Those who desire or need to suppress the odor are, for example, those who work in the presence of bad odors (for example, those who are involved in cleaning or collecting garbage); cooking odor, drainage odor, musty odor, food waste odor, body odor. Those who live in places where there are multiple different living odors, such as those who wish to suppress those multiple living odors (for example, those who live in a living room at home); Those who want to suppress odors; those who experience an environment exposed to various odors from the surroundings, such as an environment where many people are crowded in a narrow space (for example, crowded public transportation); Those who want to reduce their pleasure are mentioned.

One embodiment of the use of the BT odor suppressant in the present invention is as follows: First, for a subject who desires or needs suppression of the target odor sensation, the BT odor sensation is suppressed. The agent is applied before or with exposure to the target odor. This inhibits OR2W1 on the olfactory epithelium and causes the subject to suppress the odor sensation to the target. As a result, when the subject is exposed to the target odor, the target does not feel the odor or feels weaker (or is detected with a higher detection threshold).

The method of applying the BT odor suppressant to the subject may be any method capable of allowing the agent to reach the olfactory cells of the subject. For example, a method of volatilizing the BT odor suppressant from a composition containing the BT odor suppressant and causing the subject to inhale it, a method of atomizing a liquid containing the BT odor suppressant into fine particles and spraying the BT odor suppressant into the subject. A method of spraying or instilling a liquid containing the BT odor suppressant into the nasal cavity, a method of applying a liquid, gel, cream, ointment or the like containing the BT odor suppressant into the nasal cavity, the BT odor. Examples thereof include a method of placing a solid carrier (for example, a cotton ball) containing a sensory inhibitor in the nasal cavity.

The effective amount of the BT odor suppressant used in the present invention is not particularly limited as long as it can inhibit OR2W1 in the nasal cavity of the subject or can suppress the odor sensation of the subject. The effective amount can be appropriately adjusted according to the species and age of the subject, the original odor sensation sensitivity, the application method of the agent, the intensity and sensitivity of the target whose odor sensation is desired to be suppressed, the surrounding environment of the subject, and the like. .. However, it is preferable that the odor of the BT odor suppressant itself does not become too strong compared to the odor of the target. For example, the BT odor suppressant is preferably used at a concentration lower than the odor concentration of the target, or at a concentration lower than the odor detection threshold value of the BT odor suppressant of the subject.

For example, when the subject is to inhale the BT odor suppressant, the lower limit of the concentration of the BT odor suppressant in the subject's nasal cavity is preferably 12.0 μg / Lair, more preferably 1. .2 μg / Lair, more preferably 0.12 μg / Lair, still more preferably 0.04 μg / Lair, even more preferably 0.012 μg / Lair, while the upper limit is preferably 1000 μg / Lair. , More preferably 100 μg / Lair, still more preferably 30 μg / Lair. Alternatively, the concentration of the BT odor suppressant in the nasal cavity of the subject is preferably 12.0 to 1000 μg / Lair, 12.0 to 100 μg / Lair, or 12.0 to 30 μg / Lair. , More preferably 1.2 to 1000 μg / Lair, 1.2 to 100 μg / Lair, 1.2 to 30 μg / Lair, still more preferably 0.12 to 1000 μg / Lair, 0.12 to 100 μg. / L air, or 0.12 to 30 μg / La air, more preferably 0.04 to 1000 μg / La air, 0.04 to 100 μg / La air, or 0.04 to 30 μg / La air, and further. It is preferably 0.012 to 1000 μg / Lair, 0.012 to 100 μg / Lair, or 0.012 to 30 μg / Lair.

Further, for example, when the BT odor suppressant is volatilized from the composition containing the BT odor suppressant and sucked by the subject, the concentration of the BT odor suppressant in the composition has a lower limit. It is preferably 300 μM, more preferably 30 μM, still more preferably 3 μM, while the upper limit is preferably 300,000 μM, more preferably 30,000 μM, still more preferably 10,000 μM. Alternatively, the concentration of the BT odor suppressant in the composition is preferably 300 to 30000 μM, 300 to 30000 μM, or 300 to 10000 μM, more preferably 30 to 300,000 μM, 30 to 30000 μM, or even more preferably 30 to 10000 μM. Is 3 to 300,000 μM, 3 to 30,000 μM, or 3 to 10000 μM.

As an application example of the BT odor suppressant according to the present invention, a space where it is desired to suppress a bad odor (for example, body odor, dryness, etc.) such as a toilet, a bathroom, a ward or a nursing facility, or a residence including a kitchen, a bedroom, a closet, etc. Application to spaces where multiple different bad odors such as odors and musty odors are generated; Application to sexual environments (eg crowded public transportation); products intended to control odors (eg deodorants, external agents for deodorants, or deodorant cleaners, laundry detergents or flexible Addition to agents); Addition to products for which odor control is desired (eg, paper diapers, sanitary products, underwear, underwear, linens, masks, or other clothing, cloth products or textiles, pharmaceuticals, foods, etc.) ; For the purpose of suppressing odors, such as application to a production line of a product having a target odor or an environment in which the target odor is generated. However, the application examples of the BT odor suppressant are not limited to these.

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

[1] An odor sensation inhibitor that suppresses an odor sensation regardless of the type of odor, containing at least one selected from the group consisting of ambretto ride, muscone, and damascenone as an active ingredient.
[2] The agent according to [1], which preferably suppresses odor sensation by inhibiting OR2W1.
[3] Preferably, it is possible to suppress the odor sensation of at least one compound selected from the group consisting of compounds belonging to alcohols, azines, aldehydes, and acids.
More preferably, it can suppress the odor sensation for compounds belonging to alcohols, aldehydes, esters, azines, ketones, acids, terpenes, vanillins, benzenes and lactones.
More preferably, amines, thiols, alcohols, esters, ethers, aldehydes, cyclic alcans, terpenes, vanillins, camphors, azines, musks, ketones, acids, benzenes, lactones. Can suppress the odor sensation for compounds belonging to classes and sulfides,
The agent according to [1] or [2].
[4] An OR2W1 inhibitor containing at least one selected from the group consisting of ambrettoride, muscone, and damascenone as an active ingredient.
[5] The agent according to any one of [1] to [4], wherein the active ingredient is preferably used at a concentration lower than the detection threshold value of its own odor.
[6] A composition that volatilizes at least one selected from the group consisting of ambretteride, muscone, and damascenone, and more preferably than the group consisting of ambrettoride, muscone, and damascenone in the composition. The total concentration of at least one selected is:
The lower limit is preferably 300 μM, more preferably 30 μM, still more preferably 3 μM, and the upper limit is preferably 300,000 μM, more preferably 30,000 μM, still more preferably 10,000 μM, or
Preferably, it is 300 to 30000 μM, 300 to 30000 μM, or 300 to 10000 μM, 30 to 30000 μM, 30 to 30000 μM, 30 to 10000 μM, 3 to 300,000 μM, 3 to 30000 μM, or 3 to 10000 μM, [1] to [4]. The agent according to any one of the items.
[7] The total concentration of at least one selected from the group consisting of ambrette ride, muscone, and damascenone in the subject's nasal cavity is used to be:
The lower limit is preferably 12.0 μg / Lair, more preferably 1.2 μg / Lair, still more preferably 0.12 μg / Lair, still more preferably 0.04 μg / Lair, still more preferably 0.012 μg / Air. L air, and the upper limit is preferably 1000 μg / Lair, more preferably 100 μg / Lair, still more preferably 30 μg / Lair, or preferably 12.0 to 1000 μg / Lair, 12.0 to 100 μg /. L air, 12.0 to 30 μg / La air, 1.2 to 1000 μg / La air, 1.2 to 100 μg / La air, 1.2 to 30 μg / La air, 0.12 to 1000 μg / La air, 0. 12 to 100 μg / La air, 0.12 to 30 μg / La air, 0.04 to 1000 μg / La air, 0.04 to 100 μg / La air, 0.04 to 30 μg / La air, 0.012 to 1000 μg / L air, 0.012 to 100 μg / La air, or 0.012 to 30 μg / La air,
The agent according to any one of [1] to [4].

[8] Use of at least one selected from the group consisting of ambretteride, muscone, and damascenone in the production of an odor sensation inhibitor that suppresses odor sensation regardless of the type of odor.
[9] Use of at least one selected from the group consisting of ambrette ride, muscone, and damascenone for suppressing the odor sensation regardless of the type of odor.
[10] The use according to [8] or [9], wherein the odor sensation suppression is preferably an odor sensation suppression by inhibiting OR2W1.
[11] The odor sensation suppression is
Preferably, it enables suppression of odor sensation by at least one compound selected from the group consisting of compounds belonging to alcohols, azines, aldehydes, and acids.
More preferably, it enables compounds belonging to alcohols, aldehydes, esters, azines, ketones, acids, terpenes, vanillins, benzenes and lactones to suppress the odor sensation.
More preferably, amines, thiols, alcohols, esters, ethers, aldehydes, cyclic alcans, terpenes, vanillins, camphors, azines, musks, ketones, acids, benzenes, lactones. Allows suppression of odor sensation by compounds belonging to classes and sulfides,
Use according to any one of [8] to [10].
[12] Use of at least one selected from the group consisting of ambretteride, muscone, and damascenone in the production of OR2W1 inhibitors.
[13] Use of at least one selected from the group consisting of ambretteride, muscone, and damascenone for OR2W1 inhibition.
[14] Any of [8] to [13], preferably, at least one selected from the group consisting of ambrette ride, muscone, and damascenone is used at a concentration below the detection threshold of its own odor. Or the use described in item 1.
[15] Preferably, the agent is a composition that volatilizes at least one selected from the group consisting of the ambretteride, muscone, and damascenone, or consists of the ambretteride, muscone, and damascenone. At least one selected from the group is volatilized from the composition containing it, and the total concentration of at least one selected from the group consisting of ambretteride, muscone, and damascenone in the composition is as follows:
The lower limit is preferably 300 μM, more preferably 30 μM, still more preferably 3 μM, and the upper limit is preferably 300,000 μM, more preferably 30,000 μM, still more preferably 10,000 μM, or
It is preferably 300 to 30000 μM, 300 to 30000 μM, or 300 to 10000 μM, 30 to 30000 μM, 30 to 30000 μM, 30 to 10000 μM, 3 to 30000 μM, 3 to 30000 μM, or 3 to 10000 μM.
Use according to any one of [8] to [13].
[16] At least one selected from the group consisting of the agent or the ambretteride, muscone, and damascenone is selected from the group consisting of ambrettoride, muscone, and damascenone in the nasal cavity of the subject. Used so that the total concentration of at least one species is:
The lower limit is preferably 12.0 μg / Lair, more preferably 1.2 μg / Lair, still more preferably 0.12 μg / Lair, still more preferably 0.04 μg / Lair, still more preferably 0.012 μg / Air. L air, and the upper limit is preferably 1000 μg / Lair, more preferably 100 μg / Lair, still more preferably 30 μg / Lair, or preferably 12.0 to 1000 μg / Lair, 12.0 to 100 μg /. L air, 12.0 to 30 μg / La air, 1.2 to 1000 μg / La air, 1.2 to 100 μg / La air, 1.2 to 30 μg / La air, 0.12 to 1000 μg / La air, 0. 12 to 100 μg / La air, 0.12 to 30 μg / La air, 0.04 to 1000 μg / La air, 0.04 to 100 μg / La air, 0.04 to 30 μg / La air, 0.012 to 1000 μg / L air, 0.012 to 100 μg / La air, or 0.012 to 30 μg / La air,
Use according to any one of [8] to [13].

[17] An odor sensation suppressing method for suppressing odor sensation regardless of the type of odor, and effective at least one selected from the group consisting of ambrette ride, muscone, and damascenone for a subject who needs it. Methods, including applying in quantity.
[18] Preferably, the method according to [17], wherein the application inhibits OR2W1.
[19] The method described above
Preferably, it makes it possible to suppress the odor 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 odor sensation caused by compounds belonging to alcohols, aldehydes, esters, azines, ketones, acids, terpenes, vanillins, benzenes and lactones.
More preferably, amines, thiols, alcohols, esters, ethers, aldehydes, cyclic alkanes, terpenes, vanillins, camphors, azines, musks, ketones, acids, benzenes, lactones. It makes it possible to suppress the odor sensation due to compounds belonging to the class and sulfides.
[17] or the method according to [18].
[20] A method of inhibiting OR2W1 comprising applying in an effective amount at least one selected from the group consisting of ambretteride, muscone, and damascenone to a subject in need thereof.
[21] Preferably, at least one selected from the group consisting of Ambrette Ride, Muscone, and Damascenone is applied at a concentration below the detection threshold of its own odor, [17] to [20]. The method according to any one of the items.
[22] Preferably, the subject comprises inhaling at least one selected from the group consisting of the ambretteride, muscone, and damascenone volatilized from the composition, and the ambretteride in the composition. , Muscone, and damascenone, the total concentration of at least one selected from the group is:
The lower limit is preferably 300 μM, more preferably 30 μM, still more preferably 3 μM, and the upper limit is preferably 300,000 μM, more preferably 30,000 μM, still more preferably 10,000 μM, or
It is preferably 300 to 30000 μM, 300 to 30000 μM, or 300 to 10000 μM, 30 to 30000 μM, 30 to 30000 μM, 30 to 10000 μM, 3 to 30000 μM, 3 to 30000 μM, or 3 to 10000 μM.
The method according to any one of [17] to [20].
[23] The effective amount is: 12.0 μg / Lair, more preferably 1.2 μg / Lair, still more preferably 0.12 μg / Lair, still more preferably 0.04 μg / Lair, still more preferably 0.012 μg / Lair, and the upper limit. The values are preferably 1000 μg / Lair, more preferably 100 μg / Lair, still more preferably 30 μg / Lair, or preferably 12.0 to 1000 μg / Lair, 12.0 to 100 μg / Lair, 12. 0 to 30 μg / La air, 1.2 to 1000 μg / La air, 1.2 to 100 μg / La air, 1.2 to 30 μg / La air, 0.12 to 1000 μg / La air, 0.12 to 100 μg / L air, 0.12 to 30 μg / La air, 0.04 to 1000 μg / La air, 0.04 to 100 μg / La air, 0.04 to 30 μg / La air, 0.012 to 1000 μg / La air, 0.012 ~ 100 μg / Lair, or 0.012 ~ 30 μg / Lair,
The method according to any one of [17] to [20].

Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1 Inhibition effect of Bloody Tuned olfactory receptor OR2W1 by test substance 1) Test substance Amblet Ride (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 a human genomic DNA female (G1521: Promega) as a template. The PCR-amplified OR2W1 gene 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 incorporated into the EcoRI, XhoI site 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 allowed to stand in a clean bench for 15 minutes. To each well of the multi-well plate (96-well plate, BioCoat), 10 μL of the reaction solution was added, and then 90 μL of the HEK293 cell suspension (3 × 10 ⁵ cells / cm ² ) was added. 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 activating adenylate cyclase in conjugation with intracellular Gαs. For the measurement of the cell response in this example, a luciferase reporter gene assay was used in which an increase in the amount of intracellular cAMP was monitored as a luminescence value derived from the firefly luciferase gene (fluc2P-CRE-hygro). In addition, a gene fused with the sea luciferase gene downstream of the CMV promoter (hRluc-CMV) was simultaneously introduced into cells and used as an internal standard for correcting errors in gene transfer efficiency or cell number. The medium was removed from the cell culture prepared in 4), and 75 μL of an HBSS (GIBCO) solution containing the test substance (final concentration 100 μM) and hexanol (final concentration 10 μM), which is a known agonist of OR2W1, was added to each well (final concentration 100 μM). Test group). As a control group, an HBSS solution containing hexanol at a final concentration of 10 μM was added to the same amount of wells. As a reference (Buffer group), only the HBSS solution was added to the same volume well. The cells were cultured in a CO ₂ incubator for 4 hours to fully express the luciferase gene in the cells. Measurement of cell-derived luciferase activity was performed 4 hours after stimulation with the test substance, using a Dual-Glo ^TM luciferase assay system (Promega) according to the product operation manual. The value fLuc / hRluc, which is obtained by dividing the luminescence value fLuc derived from firefly luciferase by the luminescence value hRluc derived from sea urchin luciferase, was calculated and used as an index of cell response. The response suppression level of OR2W1 by the test substance was calculated according to the following formula.
Response suppression 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 substance is shown in FIG. Amblet Ride, Muscone, and Damascenone all suppressed the hexanol response of OR2W1 compared to the control group. From this result, it was shown that Amblet Ride, Muscone, and Damascenone are OR2W1 inhibitors.

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

The four specialized panels were asked to alternately smell the control sample and the test sample or blank, and to answer what percentage of the test sample and blank indole smell was felt compared to the control sample. All odor evaluations were performed blindly, and the order in which each test sample and blank were evaluated was random. The result of the odor evaluation is shown in FIG. The result was that the odor of the blank was felt weaker than that of the control sample due to the adaptation effect. Test substances that were answered to have a weaker odor than the blank evaluation were considered to have an odor-suppressing effect. Amblet Ride, Muscone and Damascenone all suppressed the odor of indole.

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

The control sample and the test sample or the blank were alternately smelled by three specialized panels, and how much the PEA scent of the test sample and the blank was felt as compared with the control sample was evaluated by VAS (Visual analog scale). In the VAS evaluation, the left end of the 10 cm straight line is "0 cm: I do not feel at all" and the right end is "10 cm: I feel very strongly", and the evaluator is informed of the position on the straight line where the PEA scent of each sample fits. I let you. The distance (mm) from 0 cm at the entered position was taken as the VAS measured value. All odor evaluations were performed blindly, and the order in which each test sample and blank were evaluated was random. The results are shown in FIG. The test substance evaluated to have a weaker odor than the blank was considered to have an odor suppressing effect. Amblet Ride, Muscone and Damascenone all suppressed PEA aroma.

3) Suppression of various odors by low-concentration ambretlide The effect of suppressing various odors by an ambletride solution (0.01 w / v% dipropylene glycol diluted solution) having a concentration below the detection threshold was investigated. The malodorous solution was dropped onto a 9 cm square knitted cotton cloth placed in a petri dish, and 50 μL of the ambrette ride solution was dropped around the knitted cloth so as not to overlap with the dropping point of the malodorous solution (test cloth). A control cloth without dripping ambrette ride was prepared by the same procedure. The malodorous solution was prepared as follows and used so that the odor when dropped on a cloth could be easily recognized. In the evaluation of the odor suppressing effect, 6 to 7 specialized panels evaluated the bad odor of the test cloth based on the bad odor of the control cloth by pairwise comparison between the control cloth and the test cloth. The evaluation of the malodor of the test cloth is "the malodor strength of the control cloth is stronger", "the malodor strength of the control cloth is slightly stronger", "neither can be said", and "the malodor strength of the test cloth is slightly stronger". It was performed in 5 stages of "strong" and "stronger malodor strength of the test cloth".
<Foul odor solution>
Skatole 1000ppm solution (solvent: acetone) 5μL
Isovaleric acid 1000ppm solution (solvent: water) 1 μL
Model tobacco odor solution 1 μL

The evaluation results by the specialized panel (n = 6 to 7) are shown in FIG. In the table of FIG. 4, the number of people who selected each stink stage is shown. For any of the malodors, more than two-thirds of the specialized panels evaluated that the test cloth (with ambrette ride added) had a lower malodor strength than the control cloth (without ambrette ride). From this, it was shown that Amblet Ride suppresses various odors even at a low concentration below the detection threshold.

From the results of the above examples, it is presumed that Amblet Ride, Muscone, and Damascenone have an odor-suppressing effect regardless of the type of odor, and that this odor-suppressing action is an action mediated by the inhibition of OR2W1. In addition, the odor-suppressing effect of these substances is exerted even at concentrations below the detection threshold of its own odor, suggesting that it occurs by a mechanism different from that of odor masking by its own odor. rice field.

Claims (2)

An odor suppressant that suppresses odor sensation regardless of the type of odor, containing at least one selected from the group consisting of ambrette ride, muscone, and damascenone as an active ingredient. An OR2W1 inhibitor containing at least one selected from the group consisting of ambretteride, muscone, and damascenone as an active ingredient.

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