MAS-related G protein receptor X2-mediated pruritus inhibitor

Abstract

This invention provides an anti-itch agent mediated by the MAS-related G protein receptor X2. [Solution] An itching inhibitor mediated by the MAS-related G protein receptor X2, comprising a compound selected from the group consisting of Licarin A, (2S)-Isoxanthohumol, and Neobavaisoflavone.

Description

Technical Field

[0001] The present invention relates to an itch inhibitor via MAS-related G protein-coupled receptor X2 (hereinafter also referred to as "MRGPRX2").

Background Art

[0002] Itching usually occurs when a substance that causes itching is produced in the skin first, and the substance binds to receptors on peripheral nerves distributed in the skin, activating the nerves, relayed in the spinal cord as a signal and reaching the brain, and being perceived as itching. In the itching signal transduction pathway, there are two types of pathways: the "histamine pathway" in which histamine acts as a substance that causes itching and the "non-histamine pathway" in which substances other than histamine act as substances that cause itching. Antihistamines that are involved in the histamine pathway are frequently used as drugs for suppressing itching and are used in many itching treatments. However, antihistamines are effective against urticaria, and it is difficult to suppress itching other than urticaria because the non-histamine pathway is involved in other itch (atopic dermatitis, eczema, prurigo, etc.). MRGPRX2 is known as a substance involved in non-histamine pathway itching that occurs in response to external stimuli derived from itching other than urticaria, for example, atopic dermatitis, psoriasis, contact dermatitis, nodular prurigo, sweat, etc. (Non-Patent Document 1). MRGPRX2 is a receptor on the cell membrane and is selectively expressed on mast cells and nerve cells, and particularly exists in skin mast cells. When a ligand binds to the receptor MRGPRX2 and degranulation occurs, an itching signal is transmitted to the brain.

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

[0004] Currently, only antihistamines are available as treatments to suppress itching. While effective for urticaria, they are ineffective in suppressing itching caused by non-histamine pathways, such as atopic dermatitis, psoriasis, contact dermatitis, prurigo nodule, itching caused by external stimuli like sweat, and itching associated with dryness. Therefore, there has been a need for treatments that suppress itching caused by non-histamine pathways. Therefore, the object of the present invention is to provide an antipruritic agent mediated by the MAS-related G protein receptor X2. [Means for solving the problem]

[0005] This invention relates to the following: [1] An itching inhibitor that suppresses itching involved in the non-histamine pathway, comprising a compound that inhibits MAS-related G protein receptor X2. [2] The itching inhibitor according to [1], comprising a compound selected from the group consisting of Licarin A, (2S)-Isoxanthohumol, and Neobavaisoflavone, or a derivative thereof, as the compound. [3] The itching inhibitor described in [1], wherein the itching is an itching other than urticaria. [4] The itching inhibitor described in [1], wherein the itching is itching in response to external stimuli such as atopic dermatitis, psoriasis, contact dermatitis, nodular prurigo, sweat, etc., or itching associated with dryness. [5] The itching inhibitor according to [1], wherein the signaling pathway involved is the MAPK / ERK pathway and / or the inositol phospholipid signaling pathway, in the MAS-related G protein receptor X2-mediated itching inhibitor. [6] A method for identifying a compound that modulates the MAS-related G protein receptor X2, comprising a luciferase assay and a method for measuring inositol-1-phosphate. An itch inhibitor containing a compound identified by the method of [7][6]. [Effects of the Invention]

[0006] The present invention provides an itching inhibitor mediated by the MAS-related G protein receptor X2. Because the MAS-related G protein receptor X2-mediated itching inhibitor suppresses itching via the non-histamine pathway, it can suppress itching other than urticaria, such as itching caused by external stimuli originating from atopic dermatitis, psoriasis, contact dermatitis, prurigo nodule, sweat, etc., and itching associated with dryness. [Brief explanation of the drawing]

[0007] [Figure 1] Figure 1 shows the results of the luciferase reporter assay in Test Example 1 when the compound from Formulation Example 1-1 was added. The graph shows the relationship between the concentration of the compound from Formulation Example 1-1 and the measured light intensity, relative to the light intensity of the control (agonist). [Figure 2] Figure 2 shows the results of the luciferase-based reporter assay in Test Example 1 when the compounds from Formula Example 1-2 were added. The graph shows the relationship between the concentration of the compounds from Formula Example 1-2 and the measured light intensity, relative to the light intensity of the control (agonist). [Figure 3] Figure 3 shows the results of the luciferase-based reporter assay in Test Example 1 when compounds from Formula Examples 1-3 were added. The graph shows the relationship between the concentration of compounds from Formula Examples 1-3 and the measured light intensity relative to the control (agonist) light intensity, using the control as the reference value. [Figure 4] Figure 4 shows the results of the luciferase-based reporter assay in Test Example 1 when compounds from formulation examples 1-4 were added. The graph shows the relationship between the concentration of compounds from formulation examples 1-4 and the measured light intensity relative to the control (agonist) light intensity, using the control as the reference value. [Figure 5]Figure 5 shows the results of the luciferase-based reporter assay in Test Example 1 when compounds from Formulation Examples 1-5 were added. The graph shows the relationship between the concentration of compounds from Formulation Examples 1-5 and the measured light intensity relative to the control (agonist) light intensity, which is set as the reference value. [Figure 6] Figure 6 shows the results of the luciferase-based reporter assay in Test Example 1 when compounds from formulation examples 1-6 were added. The graph shows the relationship between the concentration of compounds from formulation examples 1-6 and the measured light intensity relative to the control (agonist) light intensity, using the control as the reference value. [Figure 7] Figure 7 shows the results of the IP1 assay for Test Example 2 when the compound from Formula Example 2-1 was added, and is a graph showing the relationship between the concentration of the compound from Formula Example 2-1 and the measured concentration of inositol-1-monophosphate. [Figure 8] Figure 8 shows the results of the IP1 assay for Test Example 2 when the compound from Formula Example 2-2 was added, and is a graph showing the relationship between the concentration of the compound from Formula Example 2-2 and the measured concentration of inositol-1-monophosphate. [Figure 9] Figure 9 shows the results of the IP1 assay for Test Example 2 when the compounds from Formula Example 2-3 were added, and is a graph showing the relationship between the concentration of the compounds from Formula Example 2-3 and the measured concentration of inositol-1-monophosphate. [Figure 10] Figure 10 shows the results of the IP1 assay for Test Example 2 when the compounds from Formula Example 2-4 were added, and is a graph showing the relationship between the concentration of the compounds from Formula Example 2-4 and the measured concentration of inositol-1-monophosphate. [Figure 11] Figure 11 shows the results of the IP1 assay for Test Example 2 when the compounds from Formula Example 2-5 were added, and is a graph showing the relationship between the concentration of the compounds from Formula Example 2-5 and the measured concentration of inositol-1-monophosphate. [Figure 12] Figure 12 is a schematic diagram of the itching mechanism involving MRGPRX2. [Modes for carrying out the invention]

[0008] Embodiments of the present invention will be described below, but the present invention is not limited to the following embodiments.

[0009] The inventors of the present invention have been intensively researching for many years to suppress itching of the skin associated with drying. As a result of this research, they have come to provide a moisturizing supplement. As a result of further intensive research on the suppression of skin itching, as shown in FIG. 12, due to the decline of the barrier function on the skin surface, irritant substances from the outside such as sweat and clothes invade, and inflammatory substances etc. appear due to scratching. It has been found that the antimicrobial peptides produced therefrom bind to MRGPRX2 and degranulate, thereby causing itching. Based on this finding, by finding a method for identifying a compound that suppresses MAS-related G protein-coupled receptor X2, an itch inhibitor via MAS-related G protein-coupled receptor X2 has been completed.

[0010] The present invention relates to an itch inhibitor that suppresses itching involved in the non-histamine pathway, and an itch inhibitor containing a compound that inhibits MAS-related G protein-coupled receptor X2.

[0011] [Itch inhibitor via MAS-related G protein-coupled receptor X2] The itch inhibitor via MAS-related G protein-coupled receptor X2 is not particularly limited, but is an itch inhibitor that uses MAS-related G protein-coupled receptor X2 as a receptor and is involved in the intracellular signaling pathway of MAS-related G protein-coupled receptor X2 (hereinafter also referred to as "MRGPRX2"). The intracellular signaling pathway activated by MRGPRX2 is the cAMP / PKA pathway, the PKC pathway, Ca 2+There are the NFAT pathway, PLC pathway, PTK pathway, PKC / MEK pathway, MAPK pathway, p38MAP pathway, PI3K pathway, Rho pathway, NF-κB and JAK / STAT pathways, etc. In the pruritogens via MAS-related G protein-coupled receptor X2, the involved signal transduction pathways are not particularly limited, but preferably the MAPK pathway and / or the inositol lipid signal transduction pathway, and more preferably, the MAPK / ERK pathway and / or the inositol lipid signal transduction pathway.

[0012] [MAS-related G protein-coupled receptor X2] MAS-related G protein-coupled receptor X2 is also called "MRGX2" or "MGRG3", and refers to a member of the MRGPR (MAS-related G protein-coupled receptor) family that is expressed on mast cells and can mediate IgE-independent activation (e.g., mast cell degranulation) in response to ligand binding. An exemplary human MRGPRX2 amino acid sequence is described in Uniprot Q96LB1. MRGPRX2 is expressed in mast cells and dorsal root ganglia. MRGPRX2 is a receptor for a diverse group of ligands (or is sensitive to activation by them) including basic secretagogues, certain drugs, neuropeptides, antimicrobial peptides, and is thus important for pseudoallergic reactions, itching, pain, or inflammatory disorders upon exposure.

[0013] [MAS-related G protein-coupled receptor] MRGPRs (MAS-related G protein-coupled receptors) are G protein-coupled receptors (GPCRs), which are membrane-bound receptors that recognize the external environment in response to exogenous or endogenous signals / chemicals. These receptors can respond to multiple chemical ligands / agonists. For example, MRGPRX2 recognizes compound 48 / 80, substance P, mastoparan, icatibant, ciprofloxacin, and tracurium as agonist signals. In certain embodiments, the molecules of the present invention modulate MRGPRX2 by functioning as a reverse agonist capable of blocking multiple chemicals and / or as a competitive antagonist capable of specifically blocking individual ligands. In one embodiment, such modulation is selective for other MRGPRs such as MRGPRX1, X3, and / or X4. MRGPR is linked to different intracellular effector systems via G proteins. G proteins are heterotrimers consisting of three subunits: α (alpha), β (beta), and γ (gamma). In the inactive state, the three subunits associate, and the α subunit binds to guanosine diphosphate (GDP). When a G protein is activated, a structural change occurs, and GDP is exchanged for guanosine triphosphate (GTP). When GTP binds to the α subunit, the β and γ subunits dissociate, triggering a diverse signaling cascade.

[0014] [MAPK / ERK routes] The MAPK family, which is involved in the MAPK pathway, includes ERK (Extracellular Signal-regulated Kinase), JNK (c-Jun N-terminal kinase), and p38. The MAPK / ERK pathway is a highly conserved membrane-to-nucleus signaling module in metazoans. In the MAPK / ERK pathway involving MRGPRX2, a ligand binds to the extracellular portion of MRGPR, transmitting a signal into the cell and activating the downstream Ras. Next, Ras activates Raf, which functions as a MAP kinase kinase kinase (MAPKKK or MAP3K). Subsequently, Raf phosphorylates and activates MAP kinase kinase (MAPKK). This MAP kinase kinase (MAPKK) is called MEK (MAPK or ERK kinase) in this pathway. MEK phosphorylates and activates the third and final enzyme in this pathway, which is a MAP kinase (MAPK) called ERK (extracellular signal-regulated kinase). Once activated, ERK can move into the nucleus, where it phosphorylates transcription factors, thereby regulating their activity in important cellular processes such as growth factor-induced gene regulation, cell cycle transition, and cell differentiation.

[0015] [Serum response array (SRE)] Ternary Complex Factors (TCFs), including Elk1, are transcription factors known to be substrates of ERK. Elk1, phosphorylated by ERK, forms a complex with serum response factors (SRFs) and binds to serum response elements (SREs), resulting in the expression of numerous mitogen-inducible genes.

[0016] [Inositol phospholipid signaling pathway] In the inositol phospholipid signaling pathway, when a ligand binds to a G protein-coupled receptor, namely MRGPRX2 in this specification, the trimer G protein dissociates into a Gα subunit and a GβGγ subunit. This dissociation signal activates the enzyme PLC. Activated PLC degrades PI(4,5)P2, a phospholipid in the cell membrane, producing inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 is a water-soluble molecule that acts as an intracellular messenger. It binds to IP3 receptors in the endoplasmic reticulum, opening calcium channels and releasing calcium ions (Ca). 2+ It releases [a certain substance]. Subsequently, IP3 is broken down into inositol-1,4-diphosphate (IP2) and inositol-1-monophosphate (IP1).

[0017] [False allergic reaction] As used herein, the term “pseudoallergic reaction” refers to an IgE-independent allergic reaction characterized by histamine release, inflammation, airway constriction, or any combination thereof. A pseudoallergic reaction may be an anaphylactic reaction. Pseudoallergic reactions may be caused by a range of cationic substances, collectively referred to as basic secretagogues, including inflammatory peptides and drugs associated with allergic reactions. Accordingly, in one embodiment, an itching inhibitor mediated by the MAS-related G protein receptor X2 is provided for treating pseudoallergic reactions such as those caused by secretagogues, cationic peptide agonists, anionic peptide agonists, neutral peptide agonists, nonsteroidal antagonists, neuropeptides, and antimicrobial peptides. In one embodiment, a pseudoallergic reaction is caused by MCD peptide, substance P, VIP, PACAP, dynorphin, somatostatin, compound 48 / 80, cortistatin-14, mastoparan, meletin, cathelicidin peptide, ciprofloxacin, vancomycin, leuprolide, goserelin, histrelin, triptorelin, cetrorelics, ganirelics, degarelix, octreotide, lanreotide, pasireotide, cermorelin, tesamorelin, icatibant, glatiramer acetate, teriparatide, plumrintide, bleomycin, exenatide, glucagon, liraglutide, enfuvirtide, colistin tart, succinylcholine, tubocurarine, atracurium, mibacurium, and rocuronium.

[0018] [itch] As used herein, the term "itching" means pruritus (including acute and chronic pruritus) associated with any condition. The sensation of itching may arise, for example, from the peripheral nervous system (e.g., cutaneous or neuropathic itching) or from the central nervous system (e.g., neuropathic, nervous, or psychogenic itching). Therefore, in one embodiment, an itching inhibitor mediated by the MAS-related G protein receptor X2 is used to treat chronic itching, contact dermatitis, allergic blepharitis, anaphylaxis, anaphylactic drug reactions, anaphylactic shock, anemia, atopic dermatitis, bullous pemphigoid, candidiasis, chickenpox, end-stage renal failure, hemodialysis, cholestatic pruritus, chronic urticaria, contact dermatitis, herpetic dermatitis, diabetes, drug allergies, dry skin, dyshidrotic dermatitis, ectopic eczema, eosinophilic fasciitis, epidermolysis bullosa, erythrorhizos, food allergies, folliculitis, fungal skin infections, hemorrhoids, herpes, HIV infection, Hodgkin's disease, hyperthyroidism, and iodine production. It is provided to treat itch-related conditions such as contrast agent allergy, iron deficiency anemia, kidney disease, leukemia, porphyria, lymphoma, mast cell activation syndrome, malignant tumors, mastocytosis, multiple myeloma, neurodermatitis, onchocerciasis, Paget's disease, lice infestation, polycythemia vera, nodular prurigo, lichen planus, lichen sclerosing, anal pruritus, pseudoallergic reactions, pseudorabies, psoriasis, rectal prolapse, sarcoidosis granuloma, scabies, schistosomiasis, scleroderma, severe stress, stasis dermatitis, swimming prurigo, thyroid disease, tinea cruris, uremic pruritus, rosacea, cutaneous amyloidosis, scleroderma, acne, wound healing, burn healing, itchy eyes, and urticaria. In another embodiment, the term "itching" as used herein refers to itching that is involved in the "non-histamine pathway," in which substances other than histamine act as itching-causing agents, and is itching other than urticaria. Itching other than urticaria is not particularly limited, but itching in response to external stimuli such as atopic dermatitis, psoriasis, contact dermatitis, nodular prurigo, sweat, etc., or itching associated with dryness is preferred.

[0019] [pain] As used herein, the phrase “pain-related condition” means any pain resulting from a medical condition. Therefore, in one embodiment, a MAS-related G protein receptor X2-mediated pruritus inhibitor is used for acute pain, progressive prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, arthritis fibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis, avascular necrosis, back pain, Behset's disease (syndrome), burning mouth syndrome, bursitis, cancer pain, carpal tunnel syndrome, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical stenosis, Charcot-Marie-Tooth (CMT) disease, chronic fatigue syndrome (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, chronic pelvic pain syndrome, pulmonary collapse (pneumothorax), and complex regional pain syndrome. Crohn's disease, degenerative disc disease, toothache, Darkham's disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers-Danlos syndrome (EDS), endometriosis, eosinophilia-myalgia syndrome (EMS), erythromelalgia, fibromyalgia, gout, headache, herniated disc, hydrocephalus, intercostal neuralgia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatitis (dermatomyositis), knee injury, leg pain, hematuria syndrome, lupus, Lyme disease, medallary kidneyKidney's disease (MSK), paresthesia of the thigh, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget's disease, Personage-Turner syndrome, pelvic pain, periodontal pain, peripheral neuropathy, phantom limb pain, nerve compression, polycystic kidney disease, polymyalgia rheumatica, polymyositis, porphyria, post-hernia repair pain syndrome, post-mastectomy pain, postoperative pain, pain syndrome, post-stroke pain, post-thoracotomy pain syndrome, post-herpetic neuralgia (shingles), post-polio syndrome, primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud's disease, rheumatoid arthritis It is provided to treat pain-related conditions such as arthritis (RA), sacroiliac joint dysfunction, sarcoidosis, Scheuermann's kyphosis, sciatica, scoliosis, herpes zoster (shingles), Sjögren's syndrome, spasmodic torticollis, sphincter of Oddi dysfunction, spinocerebellar ataxia (SCA ataxia), spinal cord injury, lumbar spinal stenosis, syringomyelia, Tahlob's cyst, transverse myelitis, trigeminal neuralgia, neuropathic pain, ulcerative colitis, vascular pain, and vulvovaginal pain.

[0020] [Inflammatory disorders] As used herein, the term “inflammatory disorder” means a disease or disorder arising from and / or directed toward the tissues or organs of an individual, or their co-separation or expression, or conditions arising therefrom. Typically, there may be a variety of clinical and laboratory markers for autoimmune diseases, including, but not limited to, hypergammaglobulinemia, high levels of autoantibodies, antigen-antibody complex deposition in tissues, clinical benefits from corticosteroid or immunosuppressive therapy, and lymphoid cell aggregates in affected tissues. In one embodiment, an itching inhibitor mediated by the MAS-related G protein receptor X2 could be used to treat chronic inflammation, mast cell activation syndrome, multiple sclerosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, appendicitis, bursitis, lupus cutaneous, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (RSD / CRPS), rhinitis, tendinitis, tonsillitis, and plaque. Acne, sinusitis, rosacea, psoriasis, graft-versus-host disease, reactive airway disorder, asthma, respiratory infection, allergic rhinitis, autoinflammatory disease, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, sweat gland abscess, hypersensitivity, intestinal disorders, epithelial intestinal disorders, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, lupus erythematosus, interstitial cystitis, otitis media, pelvic inflammatory disease, endometrial pain, reperfusion injury, rheumatic fever, It is provided to treat autoimmune disorders such as rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, pneumonia, chronic obstructive pulmonary disease, persistent sputum eosinophilia, eosinophilic leukemia, eosinophilic esophagitis, eosinophilic gastritis, mast cell gastrointestinal disease, hypereosinophilic syndrome, aspirin-exacerbated respiratory disease, nasal polyposis, chronic rhinosinusitis, antibody-dependent cell-mediated cytotoxicity, neurofibromatosis, swannamatosis, tubulointerstitial nephritis, glomerulonephritis, diabetic nephropathy, allogeneic transplant rejection, amyloidosis, renal vascular ischemia, reflux nephropathy, polycystic kidney disease, hepatic fibrosis / cirrhosis, autoimmune liver disease, biliary atresia, acute and chronic hepatitis B and C viruses, liver tumors and cancer, alcoholic liver disease, polycystic liver disease, hepatobiliary tract cancer, neuromyelitis optica spectrum disorder, cardiovascular disease, and vasculitis.

[0021] [Licarin A, (2S)-Isoxanthohumol, Neobavaisoflavone] The structural formulas for Licarin A, (2S)-Isoxanthohumol, and Neobavaisoflavone are disclosed together as formulas I, II, and III, respectively. [ka] [ka] [ka] MAS-related G protein receptor X2-mediated pruritus inhibitors are pruritus inhibitors comprising compounds selected from the group consisting of Licarin A, (2S)-Isoxanthohumol, and Neobavaisoflavone. The IUPAC name for Licarin A (CAS number: 51020-86-1) is 2-methoxy-4-[(2S,3S)-7-methoxy-3-methyl-5-[(1E)-propa-1-enyl]-2,3-dihydro-1-benzofuran-2-yl]phenol. The IUPAC name for (2S)-Isoxanthohumol (CAS number: 70872-29-6) is (2S)-7-hydroxy-2-(4-hydroxyphenyl)-5-methoxy-8-(3-methylbuta-2-enyl)-2,3-dihydrochroman-4-one. The IUPAC name for Neobavaisoflavone (CAS number: 41060-15-5) is 7-hydroxy-3-(4-hydroxy-3-(3-methylbuta-2-enyl)phenyl)chromen-4-one. The amount of licarin A, (2S)-isoxanthohumol, or neobavaisoflavone added to the MAS-related G protein receptor X2-mediated pruritus inhibitor is preferably 0.01% to 99% by mass, more preferably 0.1% to 80% by mass, and even more preferably 1% to 60% by mass, relative to the total amount of the formulation. Two or more of these compounds can also be added in combination.

[0022] In this specification, “modulation” means that a compound interacts with MRGPRX2 so as to function as a reverse agonist to the receptor and / or a competitive antagonist to the receptor. In one embodiment, such modulation is partially or completely selective to other MRGPRs such as MRGPRX1, X3 and / or X4.

[0023] Japanese Patent Publication No. 2023-542541 lists N-[(1R,3S)-3-[6-fluoro-2-(trifluoromethyl)quinoline-4-yl]amino}cyclohexyl]-3-methanesulfonamidebenzamide as modulators for adjusting MRGPRX2, and discloses administering a pharmaceutical composition containing the above compound as a method for treating MRGPRX2 or MRGPRX2 ortholog-dependent conditions, such as pseudoallergic reactions and itchiness-related conditions. However, Licarin A, (2S)-Isoxanthohumol, and Neobavaisoflavone are not listed. Furthermore, in Example 29 of paragraph

[0499] of Japanese Patent Publication No. 2023-542541, it is disclosed that MRGPRX2 antagonist activity was investigated using cells stably expressing human MRGPRX2 and the IP-One-Gq kit (part number 62IPAPEJ) purchased from Cisbio. The IP-One-Gq kit used detects inositol-1-monophosphate. From this, it is suggested that the modulator for regulating MRGPRX2 related to Japanese Patent Publication No. 2023-542541 affects the accumulation of inositol-1-monophosphate, but there is no disclosure or suggestion that the modulator for regulating MRGPRX2 is involved in the MAPK / ERK pathway.

[0024] (Application) Itch inhibitors mediated by the MAS-related G protein receptor X2 can be used in cosmetics, quasi-drugs, medical supplies, hygiene products, pharmaceuticals, supplements, and the like. It is expected that antipruritic agents, acting via the MAS-related G protein receptor X2, can suppress itching associated with the non-histamine pathway.

[0025] The itch inhibitors mediated by the MAS-related G protein receptor X2 may consist only of licarin A, (2S)-Isoxanthohumol, and neobavaisoflavone, but plant extracts containing these components can also be used. In addition, known excipients, fragrances, colorants, emulsifiers, stabilizers, thickeners, enzymes, preservatives, antibacterial agents, lubricants, surfactants, disintegrants, disintegration inhibitors, binders, absorption enhancers, adsorbents, humectants, solubilizers, preservatives, flavorings, sweeteners, UV absorbers, etc., may be added as needed, within limits that do not impair the above effects.

[0026] (Method of administration) Methods of administering MAS-related G protein receptor X2-mediated pruritus inhibitors include oral administration, injection, sublingual administration, and rectal administration. Additionally, ointments, patches, eye drops, eye ointments, nasal sprays, aerosol formulations, vaginal tablets, etc., can be applied to the skin, eyes, vagina, and other mucous membranes, allowing the MAS-related G protein receptor X2-mediated pruritus inhibitor to act directly on the contact site.

[0027] (cosmetics) When an itching inhibitor mediated by the MAS-related G protein receptor X2 is used as a cosmetic ingredient, it can be prepared into various desired dosage forms such as liquids (aqueous solutions, lotions, sprays, suspensions, and emulsions), solids (powder, granules, and blocks), semi-solids (creams and pastes), and gels. Such cosmetics are useful as basic cosmetics such as facial cleansers, lotions, creams, gels, essences (serums), packs and masks, makeup cosmetics such as foundations and lipsticks, oral cosmetics, fragrance cosmetics, hair cosmetics, and body cosmetics.

[0028] These cosmetics can be manufactured in accordance with conventional methods. Furthermore, the amount, method, and timing of the aqueous solution in the cosmetics can be appropriately selected. In addition, they can be sealed in appropriate containers such as bottles, bags, cans, spray cans, atomizers, boxes, or packs, as needed.

[0029] When using an itching inhibitor mediated by the MAS-related G protein receptor X2 as a cosmetic ingredient, it can be used with commonly used known ingredients added as appropriate. For example, natural and synthetic surfactants such as anionic surfactants (fatty acid soaps, sulfonate-type anionic surfactants, sulfate-type anionic surfactants, phosphate-type anionic surfactants, acylmethyl taurate salts, monoalkyl phosphates, acyl glutamate salts, isethionate salts, etc.), cationic surfactants (amine-type cationic surfactants, quaternary ammonium-type cationic surfactants (tetraalkylammonium type, pyridinium type), nonionic surfactants (glycerin fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan tetraoleate, polyoxyethylene alkyl ethers, polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene alkyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyglycerin fatty acid esters, etc.), amphoteric surfactants (imidazoline type, betaine type, amino acid type), fluorine-based surfactants, silicone-based surfactants, and alginic acid. Sodium, propylene glycol alginate, gum arabic, xanthan gum, pectin, tragacanth, sodium carboxymethylcellulose, methylcellulose, carboxyvinyl polymer, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, cationized cellulose, cationized dextran, cationized dextrin, chitosan, cationized vinylpyrrolidone polymer, N,N-dimethyl-3,5-methylenepiperidinium chloride polymer, milk protein, soy protein, gelatin, egg protein, sodium caseinate, Water-soluble polymers such as whey protein, Ginkgo biloba, Centella asiatica, Licorice, Carrot, Scutellaria baicalensis, Scutellaria indica, Alpinia japonica, Licorice fraction, Gokahi, Senpukuka, Hikai, Daphniphyllum macropodum, Chamomile, Horse chestnut, Escin, Terminalia, Ruscogenin, Butcher's broom, Cola, Guarana, Yerba mate, Coffee, Cacao, Plectranthus, Salvia miltiorrhiza, Bisnaga, Silymarin, Leucocyanin, St. John's wort, Rhus sylvestris, Perilla, Scutellaria baicalensis, Schizonepeta tenuifolia, Rosemary, Sage, Thyme, Artemisia princeps, Artemisia capillaris, Atractylodes macrocephala, Achillea millefolium, Lithospermum erythrorhizon, Fennel,Plant components such as Phellodendron bark, Ginger, Angelica root, Cnidium officinale, Citrus unshiu, Valerian, Angelica tree, Picea, Peony, Safflower, Iris, Poria cocos, and Peppermint; active ingredients such as succinic acid, fumaric acid, citric acid, pyruvic acid, glucuronic acid, 2-hydroxybutyric acid, lactic acid, malic acid, tartaric acid, tartonic acid, methyl pyruvate, ethyl pyruvate, vitamin A acid, vitamin C derivatives, vitamin D, vitamin E, oligopeptides, tranexamic acid esters; polyhydric alcohols, amino acids, mucopolysaccharides, proteins, biological extracts, fermentation metabolites, polysaccharides, plant extracts, and phospholipids. Antiglycation agents such as ceramides, oils and fats (natural oils such as soybean oil, rice bran oil, jojoba oil, avocado oil, almond oil, cocoa oil, olive oil, sesame oil, peach kernel oil, castor oil, coconut oil, mink oil, beef tallow, lard, etc., hydrogenated oils obtained by hydrogenating these natural oils and fats, and synthetic triglycerides and diglycerides such as myristic acid glyceride and 2-ethylhexanoic acid glyceride), waxes (carnauba wax, whale wax, beeswax, lanolin, etc.), hydrocarbons (liquid paraffin, petrolatum, paraffin, microcrystalline wax, ceresin, squalane, pruritus). (Stan, etc.), higher fatty acids (lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, linolenic acid, lanolinic acid, isostearic acid, etc.), higher alcohols (lauryl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, cholesterol, 2-hexyldecanol, etc.), esters (cetyl octanoate, myristyl lactate, cetyl lactate, isopropyl myristate, myristyl myristate, isopropyl palmitate, isopropyl adipate, butyl stearate, oleic acid), Decyl acid, cholestyryl isostearate, etc.), essential oils (peppermint oil, jasmine oil, iris oil, cypress oil, spruce oil, limon oil, turpentine oil, cinnamon oil, bergamot oil, mandarin orange oil, iris oil, pine oil, lavender oil, bay leaf oil, clove oil, hinoki cypress oil, rose oil, eucalyptus oil, lemon oil, peppermint oil, thyme oil, rose oil, sage oil, menthol, cineole, eugenol, citral, citronellal, borneol, linalool, geraniol, camphor, thymol, spiranthol, pinene, limonene, terpene compounds, etc.),Oils and fats such as silicone oils (emollients), inorganic salts such as sodium carbonate, sodium bicarbonate, sodium sesquicarbonate, borax, sodium sulfate, sodium sulfide, sodium nitrate, sodium thiosulfate, sodium polyphosphate, sodium phosphate, potassium chloride, potassium sulfide, calcium oxide, magnesium oxide, calcium carbonate, magnesium carbonate, inorganic acids such as boric acid, metasilicic acid, anhydrous silicic acid, Yellow No. 4, Blue No. 1, Yellow No. 202, chlorophyll, riboflavin, safflower, crocin, anthraquinone, etc. Examples include pigments, fragrances, polymers such as acrylic resins, styrene resins, epoxy resins, nylon, polyethylene, polypropylene, polyvinyl chloride, polyethylene terephthalate resin, and polytetrafluoroethane, copolymers of these polymers, fine powders such as silicic acid, calcium silicate, natural aluminum silicate, synthetic aluminum silicate, zeolite, titanium dioxide, talc, kaolin, mica, and bentonite, sulfur, mineral deposits, mineral sand, mica powder, neutral clay, roasted rice bran, disinfectants, preservatives, and other ingredients necessary for formulation.

[0030] (Quasi-drugs, medical supplies, hygiene products, pharmaceuticals) When using MAS-related G protein receptor X2-mediated itching inhibitors as ingredients for quasi-drugs, medical supplies, hygiene products, or pharmaceuticals, they can be prepared in various desired dosage forms, such as liquids (aqueous solutions, lotions, sprays, suspensions, and emulsifiers), solids (powder, granules, and blocks), semi-solids (creams and pastes), and gels.

[0031] Specifically, these include basic cosmetics such as ointments, compresses, lotions, emulsions, creams, oils, and masks; hair cosmetics such as facial cleansers, shampoos, conditioners, hair treatments, hair creams, pomades, hairsprays, hair styling products, perming agents, hair tonics, hair dyes, and hair growth / nourishing products; makeup cosmetics such as foundations, face powders, lipsticks, blushes, eyeshadows, eyeliners, mascaras, eyebrow pencils, and eyelash products; finishing cosmetics such as nail polish; perfumes; bath products; and other items such as toothpastes, mouthwashes and gargles, deodorants and odor control agents, hygiene products, sanitary cotton, and wet wipes.

[0032] These quasi-drugs, medical supplies, sanitary supplies, and pharmaceuticals may be manufactured in accordance with conventional laws, using, as necessary, known auxiliary agents that are commonly used in the relevant art, such as fillers, bulking agents, excipients, binders, humectants, disintegrants, surfactants, lubricants, colorants, flavoring agents, solubilizers, suspending agents, and coating agents. They may also contain colorants, preservatives, fragrances, flavoring agents, sweeteners, and other quasi-drugs, medical supplies, sanitary supplies, and pharmaceuticals.

[0033] When using MAS-related G protein receptor X2-mediated itch inhibitors as ingredients for quasi-drugs, medical supplies, hygiene products, or pharmaceuticals, they may contain various known components and additives commonly used in these products, depending on the purpose. For example, it may contain higher alcohols, silicones, waxes, oils, alcohols, esters, metal soaps, gums, water-soluble polymer compounds, surfactants, vitamins, amino acids, as well as extracts and extracts of animals, plants, and herbal medicines, microbial culture metabolites such as yeast extracts, pigments, astringents, disinfectants, fragrances, colorants, sweeteners, hormones, metal ion sequestering agents, pH adjusters, chelating agents, preservatives, cooling agents, stabilizers, emulsifiers, animal and plant proteins and their breakdown products, animal and plant polysaccharides and their breakdown products, animal and plant glycoproteins and their breakdown products, blood flow promoters, anti-inflammatory and anti-allergic agents, cell activators, keratolytic agents, wound healing agents, foaming agents, thickeners, oral preparations, deodorizers, bittering agents, seasonings, enzymes, and the like.

[0034] While itching inhibitors mediated by the MAS-related G protein receptor X2 are preferred for use in humans, they can also be applied to non-human animals as long as the above-mentioned effects are achieved.

[0035] (supplement) A supplement is a food category consisting of dietary supplements, and in this specification, it refers to a functional aid that can provide effects such as suppressing itching involved in the non-histamine pathway. When using an antipruritic agent mediated by the MAS-related G protein receptor X2 as a supplement ingredient, it can be in solid, gel, or liquid form. Examples of supplement forms include various processed foods and beverages, powders, tablets, pills, capsules, jellies, and granules.

[0036] When using an itching inhibitor mediated by the MAS-related G protein receptor X2 as a supplement ingredient, it may contain excipients such as dextrin, preservatives such as vitamin C, flavorings such as vanillin, pigments such as safflower pigment, monosaccharides, oligosaccharides and polysaccharides (e.g., glucose, fructose, sucrose, saccharose, and carbohydrates containing these), acidulants, flavorings, oils and fats, emulsifiers, whole milk powder, or additives such as agar. Two or more of these components may be used in combination, and synthetic products and / or large amounts thereof may be included.

[0037] When using an antipruritic agent mediated by the MAS-related G protein receptor X2 as a supplement ingredient, it can be manufactured according to conventional methods. Furthermore, the amount, method, and timing of inclusion in the supplement can be selected as appropriate. Additionally, it can be sealed in suitable containers such as bottles, bags, cans, boxes, or packs, as needed.

[0038] As described above, the present invention has been described by embodiments, but the discussions that constitute part of this disclosure should not be understood as limiting the invention. Various alternative embodiments, examples, and operational techniques will become apparent to those skilled in the art from this disclosure. In the embodiments described above, the focus has been on orally administered agents as itch inhibitors. However, itch inhibitors are not limited to orally administered agents and may also be used in parenterally administered forms, such as by injection, transdermal administration, or transdermal absorption forms such as patches. [Examples]

[0039] The present invention will be described in more detail below based on examples. However, the scope of the present invention is not limited by these examples. In Test Example 1 and Test Example 2, the corresponding examples are Formulation Examples 1-1 to 1-3 and Formulation Examples 2-1 to 2-3, respectively.

[0040] [Test Example 1: Luciferase Assay] 1. Test substance The test substances were selected from Med Chem Express's natural product library, and 5584 compounds were prepared. Representative examples of these 5584 compounds are shown in formulation examples 1-1 to 1-6 below. • Prescription example 1-1: Licarin A • Prescription examples 1-2: (2S)-Isoxanthohumol • Prescription examples 1-3: Neobavaisoflavone • Prescription examples 1-4: Geraniin (CAS number: 60976-49-0) • Prescription examples 1-5: Deguelin (CAS number: 522-17-8) • Example prescription 1-6: 3-O-acetyl-11-hydroxy-beta-boswellic acid (CAS number: 146019-25-2)

[0041] 2. Reagents, plasmid vectors Cortistatin-14 (CAS number: 186901-48-4) was purchased from Med Chem Express. The pcDNA3.1 expression vector (pcDNA3.1 3HA-MRGPRX2), designed to affix three hemagglutinin (HA) epitope tags to the N-terminus of human MRGPRX2, was obtained from GenScrip (catalog number: OHu14022). The luciferase reporter vector (pGL4.33[luc2P / SRE / Hygro]), which ligates a Serum Response Element (hereinafter referred to as "SRE"), a sequence that responds to the MAP / ERK pathway, to the promoter region, was obtained from Promega Corporation.

[0042] 3. Production of cells stably expressing SRE and HA-MRGPRX2 Human kidney-derived HEK293 cells cultured in 10% FBS-containing DMEM were transfected with the obtained plasmid pGL4.33[luc2P / SRE / Hygro] using FuGENE®HD (manufactured by Promega Corporation). After 48 hours, hygromycin B (manufactured by Fujifilm Wako Pure Chemical Corporation) was added to achieve a final concentration of 0.25 mg / ml, and cells that acquired hygromycin B resistance were designated as SRE-stable expressing cells (hereinafter referred to as "HEK / SRE cells"). Furthermore, the established HEK / SRE cells were transfected with the plasmid pcDNA3.1 HA-MRGPRX2, and cells that acquired resistance to 0.25 mg / ml of hygromycin B and 50 mg / ml of G418-sulfate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) after 48 hours were used in experiments as SRE / MRGPRX2 stable expression cells (hereinafter referred to as "HEK / SRE / MRGPRX2 cells").

[0043] 4. Reporter assay using luciferase HEK / SRE / MRGPRX2 cells were seeded at 2 × 10^4 cells / well in a clear-bottomed 96-well white plate (Corning International) and cultured for 24 hours. The test substance was diluted 3-fold in 8 steps using DMSO to obtain final concentrations ranging from 0.0045 to 10 μM. 10 μL / well of DMSO diluted with 1% FBS-containing DMEM or the test substance was added, followed by 10 μL / well of an agonist (Cortistatin-14, final concentration 10 μM) diluted with 1% FBS-containing DMEM. The test substance and the control, Cortistatin-14, were added to achieve a DMSO concentration of 0.1%. Six hours after adding the test substance and Cortistatin-14, 50 μL / well of the Bright-Glo Luciferase Assay System (manufactured by Promega Corporation) was added, and luminescence measurements were performed using a luminometer (Tecan Corporation, model number: INFINITE® M200PRO). The light intensity measured under conditions where the test substance was added was relative to the light intensity of the agonist (control) as a baseline. Test substances that showed a decrease in signal intensity due to toxicity were excluded from the evaluation.

[0044] 5.Results The results obtained in Test Example 1 are shown in Figures 1 to 6.

[0045] As shown in Figure 1, when formulation example 1-1 was used as the test substance, the luminescence intensity of luciferase induced by cortistatin-14 was inhibited in a concentration-dependent manner by the compound in formulation example 1-1. As shown in Figure 2, when formulation examples 1-2 were used as test substances, the luminescence intensity of luciferase induced by Cortistatin-14 was inhibited in a concentration-dependent manner by the compounds in formulation examples 1-2. As shown in Figure 3, when formulations 1-3 were used as test substances, the luminescence intensity of luciferase induced by Cortistatin-14 was inhibited in a concentration-dependent manner by the compounds in formulations 1-3. As shown in Figure 4, when formulations 1-4 were used as test substances, the luminescence intensity of luciferase induced by Cortistatin-14 was inhibited in a concentration-dependent manner by the compounds in formulations 1-4. As shown in Figure 5, when formulations 1-5 were used as test substances, the luminescence intensity of luciferase induced by Cortistatin-14 was inhibited in a concentration-dependent manner by the compounds in formulations 1-5. As shown in Figure 6, when formulation examples 1-6 were used as test substances, the luciferase luminescence intensity induced by Cortistatin-14 was not inhibited. In other words, Licarin A, (2S)-Isoxanthohumol, Neobavaisoflavone, Geraniin, and Deguelin were found to have MAP / ERK pathway-dependent MRGPRX2 inhibitory activity. Similar results were obtained with six other compounds besides Licarin A, (2S)-Isoxanthohumol, Neobavaisoflavone, Geraniin, and Deguelin, as seen in formulations 1-1 to 1-5. As a result, in Test Example 1, it was found that 11 compounds, including Licarin A, (2S)-Isoxanthohumol, Neobavaisoflavone, Geraniin, and Deguelin, out of 5584 compounds selected from Med Chem Express's natural product library, exhibit MAP / ERK pathway-dependent MRGPRX2 inhibitory activity.

[0046] [Test Example 2: IP1 Assay] 1. Test substance The test substances used were 11 compounds that showed MAP / ERK pathway-dependent MRGPRX2 inhibitory activity in Test Example 1. Representative examples of these 11 compounds are shown in Formulation Examples 2-1 to 2-5 below. • Prescription example 2-1: Licarin A • Prescription example 2-2: (2S)-Isoxanthohumol • Prescription example 2-3: Neobavaisoflavone • Prescription example 2-4: Geraniin (CAS number: 60976-49-0) • Prescription example 2-5: Deguelin (CAS number: 522-17-8)

[0047] 2. Reagents, plasmid vectors Cortistatin-14 (CAS number: 186901-48-4) was purchased from Med Chem Express. The plasmid vector used was the same as that used in Experiment 1.

[0048] 3. Cell culture and transfection Human kidney-derived HEK293 cells cultured in 10% FBS-containing DMEM were transfected with the pcDNA3.1 HA-MRGPRX2 plasmid obtained above using FuGENE® HD (manufactured by Promega Corporation). After 48 hours, G418-sulfate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added to achieve a final concentration of 50 mg / ml, and the cells that acquired resistance to G418-sulfate were used in experiments as MRGPRX2 stably expressing cells (hereinafter referred to as "HEK / MRGPRX2 cells").

[0049] 4. IP1 assay Inositol-1-monophosphate (hereinafter referred to as "IP1") was measured using an IP1 assay kit (product name "AlphaLISA® IP-One Detection Kit", manufactured by PerkinElmer). The IP1 assay procedure was performed as follows (1) to (6) below. (1) HEK / MRGPRX2 cells were diluted with Stimulation Buffer from the IP1 measurement kit and seeded at 5 × 10^4 / well in a 1 / 2 area 96-well white plate (Revvity). (2) The IP1 standard was serially diluted with Stimulation Buffer and added to the wells for the standard curve at a rate of 10 μL / well. (3) In a 96-well plate, either the antagonist (test substance) diluted 100-fold with Stimulation Buffer or 10 μL of Stimulation Buffer, and either the agonist (Cortistatin-14) or Stimulation Buffer were added at 10 μL / well, and the mixture was incubated at 37°C for 2 hours with shaking. (4) 10 μL / well of biotinylated IP1 and Anti-IP1 AlphaLISA® Acceptor beads, included in the kit, diluted 50-fold with Immunoassay Buffer. After spinning down, the mixture was incubated at 23°C in the dark for 90 minutes with shaking. (5) 10 μL of AlphaLISA® Streptavidin-coated Donor beads diluted 25-fold with Immunoassay Buffer was added, the mixture was spun down, and then incubated at 23°C in the dark for 60 minutes while shaking. (6) The 96 wells were read using an HTRF®-compatible plate reader (PerkinElmer, model number: EnVision2105, 615nm), and the IP1 concentration released from the cells was measured.

[0050] 5.Results The results obtained in Test Example 2 are shown in Figures 7 to 11.

[0051] As shown in Figure 7, the increase in IP1 concentration caused by Cortistatin-14 was significantly suppressed by the addition of the compound in formulation example 2-1, in proportion to the compound concentration. As shown in Figure 8, the increase in IP1 concentration caused by Cortistatin-14 was significantly suppressed by the addition of the compound in formulation example 2-2, in proportion to the compound concentration. As shown in Figure 9, the increase in IP1 concentration caused by Cortistatin-14 was significantly suppressed by the addition of the compounds in formulation examples 2-3, in proportion to the compound concentration. As shown in Figure 10, when the compounds from formulation example 2-4 were added, no significant suppression proportional to the compound concentration was observed in the increase in IP1 concentration caused by Cortistatin-14. As shown in Figure 11, when the compounds from formulation example 2-5 were added, no significant suppression proportional to the compound concentration was observed in the increase in IP1 concentration caused by Cortistatin-14. Specifically, Licarin A, (2S)-Isoxanthohumol, and Neobavaisoflavone were found to have MRGPRX2 inhibitory activity dependent on the inositol phospholipid signaling pathway. In contrast, Geraniin and Deguelin, which showed MAP / ERK pathway-dependent MRGPRX2 inhibitory activity in Test Example 1, similar to Licarin A, (2S)-Isoxanthohumol, and Neobavaisoflavone, were found to lack inositol phospholipid signaling pathway-dependent MRGPRX2 inhibitory activity. Furthermore, six other compounds besides those in Formula Examples 1-1 to 1-5 yielded similar results to Formula Examples 1-4 and 1-5, indicating that they lacked inositol phospholipid signaling pathway-dependent MRGPRX2 inhibitory activity. Test Example 2 revealed that among the 11 compounds that showed MAP / ERK pathway-dependent MRGPRX2 inhibitory activity in Test Example 1, Licarin A, (2S)-Isoxanthohumol, and Neobavaisoflavone exhibited inositol phospholipid signaling pathway-dependent MRGPRX2 inhibitory activity.

[0052] The results from Test Examples 1 and 2 revealed that Licarin A, (2S)-Isoxanthohumol, and Neobavaisoflavone have MAP / ERK pathway-dependent and / or inositol phospholipid signaling pathway-dependent MRGPRX2 inhibitory activity. Since MRGPRX2 is involved in non-histamine pathway itching, it is thought that non-histamine pathway itching can be suppressed by using licarin A, (2S)-Isoxanthohumol, and neobavaisoflavone through MRGPRX2 inhibition. [Industrial applicability]

[0053] The MAS-related G protein receptor X2-mediated itch inhibitor obtained from the present invention suppresses itching via the non-histamine pathway, and can therefore suppress itching other than urticaria that could not be suppressed by antihistamines, such as itching caused by external stimuli originating from atopic dermatitis, psoriasis, contact dermatitis, prurigo nodule, sweat, etc., and itching associated with dryness.

Claims

1. An antipruritic agent that suppresses itching involved in the nonhistamine pathway, An antipruritic containing a compound that inhibits MAS-related G protein receptor X2.

2. The itch inhibitor according to claim 1, wherein the compound comprises a compound selected from the group consisting of Licarin A, (2S)-Isoxanthohumol, and Neobavaisoflavone, or a derivative thereof.

3. The itch inhibitor according to claim 1, wherein the aforementioned itching is an itching other than urticaria.

4. The itching inhibitor according to claim 1, wherein the itching is itching in response to external stimuli such as atopic dermatitis, psoriasis, contact dermatitis, nodular prurigo, sweat, etc., or itching associated with dryness.

5. The itching inhibitor according to claim 1, wherein the signaling pathway involved is the MAPK / ERK pathway and / or the inositol phospholipid signaling pathway, in the MAS-related G protein receptor X2-mediated itching inhibitor.

6. A method for identifying compounds that regulate MAS-related G protein receptor X2, Luciferase assay and, A method for identifying the compound, comprising a method for measuring inositol-1-phosphate.

7. An itch inhibitor comprising a compound identified by the method of claim 6.

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