WO2021002352A1 - Composition for treating or preventing tardive dyskinesia, and method for screening active ingredient for treating or preventing tardive dyskinesia - Google Patents

Abstract

Provided are a composition for treating or preventing tardive dyskinesia and a method for screening an active ingredient for treating or preventing tardive dyskinesia. More specifically, provided are: a composition for treating or preventing tardive dyskinesia, said composition comprising a TRPV1 agonist or a prodrug thereof as an active ingredient; and a method for screening an active ingredient for treating or preventing tardive dyskinesia, said method comprising using the activation of TRPV1 as an indicator.

Description

Compositions for treating or preventing tardive dyskinesia, and methods for screening active ingredients for treating or preventing tardive dyskinesia.

The present disclosure relates to a composition for treating or preventing tardive dyskinesia. The present disclosure also relates to a method for screening an active ingredient for treating or preventing tardive dyskinesia.

Dyskinesia is a type of involuntary movement that appears on the face, etc., and is caused by the use of antipsychotic drugs (for example, antidopamine drugs). Dyskinesia (this is called tardive dyskinesia) and antiparkinson's disease. It is roughly divided into two types of dyskinesia caused by the use of dopamine-related drugs such as drugs. Both are said to be diseases with similar symptoms but completely different causes and treatment methods.

Tardive dyskinesia has been reported to occur primarily with long-term use of antidopamines, including repeated purging of the lips, left and right movement of the tongue, muffled mouth, sticking out of the mouth, and clenching teeth. It is known that symptoms are observed and the frequency of onset increases with long-term administration (Non-Patent Document 1). Currently, the only way to treat tardive dyskinesia is to stop taking the causative drug or change to another drug, and the development of an effective therapeutic drug is desired.

It is an object of the present disclosure to provide a novel composition for treating or preventing tardive dyskinesia. It is also an object of the present disclosure to provide a method for screening an active ingredient for treating or preventing tardive dyskinesia.

Since the combined use of an antidopamine drug and acetaminophen reduces the incidence of tardive dyskinesia, the present inventors have found that an agonist of TRPV1 has a therapeutic or preventive effect on tardive dyskinesia, and further improved it. Was piled up.

The present disclosure includes, for example, the subjects described in the following sections.
Item 1.
A composition for treating or preventing tardive dyskinesia, which comprises an agonist of TRPV1 or a prodrug thereof as an active ingredient.
Item 2.
The following general formula (1)

[In the formula, R ¹ represents a hydrogen atom or a lower alkyl group. n represents an integer of 1-4, and when n represents an integer of 2 or more, n pieces of R ¹ may be the same or different. R ² represents an aliphatic hydrocarbon group having 1 to 25 carbon atoms, in which a hydrogen atom may be substituted with a hydroxyl group. X represents an imino (-NH-) group, a methylene group, or an oxygen atom. When a indicates an integer of 1 to 5, and a indicates an integer of 2 or more, a Xs may be the same or different. ]
A composition for treating or preventing tardive dyskinesia, which comprises the compound represented by (1) or a salt thereof as an active ingredient.
Item 3.
Item 2. The composition according to Item 1 or 2, which is for oral administration or intravenous injection.
Item 4.
A method for screening an active ingredient for treating or preventing tardive dyskinesia, using the activation of TRPV1 as an index.

For example, a composition for treating or preventing tardive dyskinesia can be provided. In addition, for example, a method for screening an active ingredient for treating or preventing tardive dyskinesia can be provided.

It shows the preventive effect of acetaminophen on tardive dyskinesia induced by haloperidol. It shows the therapeutic effect of acetaminophen on tardive dyskinesia induced by haloperidol. The results of examining the effect of acetaminophen on the effect of haloperidol on schizophrenia are shown. It shows the therapeutic effect of AM404 on tardive dyskinesia induced by haloperidol. The results of investigating the effect of TRPV1 on the therapeutic effect of acetaminophen on tardive dyskinesia are shown. It shows the therapeutic effect of orbanil on tardive dyskinesia induced by haloperidol. It shows the therapeutic effect of Albanil on tardive dyskinesia induced by haloperidol. The results of investigating the effect of TRPV1 on the therapeutic effect of capsaicin on tardive dyskinesia are shown. It shows the therapeutic effect of capsaicin on tardive dyskinesia induced by haloperidol. It shows the therapeutic effect of phenacetin on tardive dyskinesia induced by haloperidol.

Hereinafter, each embodiment included in the present disclosure will be described in more detail.

In the present disclosure, tardive dyskinesia is dyskinesia caused by the use of antipsychotic drugs. Examples of antipsychotic drugs include antidopamine drugs. Anti-dopamine drugs include, for example, haloperidol or a salt thereof or an ester thereof, pariperazole or a salt thereof or an ester thereof, chlorpromazine or a salt thereof, levomepromazine or a salt thereof, perphenazine or a salt thereof, flufenazine or a salt thereof, prochlorperazine. Or its salt, propericiadin or its salt, bromperidol or its salt, pipamperon or its salt, spiperon or its salt, timiperon or its salt, sulpyrido or its salt, thrutpride or its salt, thiaprid or its salt, nemonapride or Its salt, risperidone or its salt, perospyrone or its salt, bronanserin or its salt, olanzapine or its salt, quetiapine or its salt, crozapine or its salt, acenapine or its salt, aripiprazole or its salt, aripiprazole or its salt, Zotepine or its salt, pimodide or its salt, clocaplamin or its salt, mosapramine or its salt, oxypertin or its salt, chromipramine or its salt, nortryptrin or its salt, amitriptilin or its salt, amoxapine or its salt, imipramine or its salt Examples thereof include trimipramine or a salt thereof, lofeplamine or a salt thereof, dosrepin or a salt thereof, myanserin or a salt thereof, maprotyrin or a salt thereof, cetiptilin or a salt thereof, metocropramide or a salt thereof, donperidone or a salt thereof, itopride or a salt thereof, and the like. ..

The present disclosure includes a composition containing an agonist of TRPV1 (transient recipient potential cation channel subfamily V member 1) or a prodrug thereof as an active ingredient. Hereinafter, the composition may be referred to as "the composition of the present disclosure".

TRPV1 is a highly calcium ion-permeable non-selective cation channel with a 6-transmembrane region belonging to the Transient Receptor Protein (TRP) superfamily, and is also called vanilloid receptor 1 (VR1) or capsaicin receptor. is there.

In the present disclosure, the agonist of TRPV1 includes not only a compound exhibiting an agonistic action on TRPV1 but also a compound exhibiting a partial agonistic action.

The agonist of TRPV1 is not particularly limited as long as it is a compound exhibiting the above-mentioned action. For example, AM404, capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, nonibamide, piperin, eugenol, leciniferatoxin, gingerol, vanillylacetone, evodiamine, cannavidiol, polygodial, isoveleral, cypress, vanilox. Capsaicin, shogaol, sanshool, alicin, anandamide, N-arachidonyl dopamine (NADA), N-oleoyl dopamine (OLDA), oleoyl ethanolamide, omega-3 polyunsaturated fatty acid, 2-aminoethoxydiphenylborate (2-APB), propofol, lidocain, orbanyl, Albanil and the like. These can be used alone or in combination of two or more.

In the present disclosure, the prodrug of an agonist of TRPV1 means a compound that exhibits an agonistic action of TRPV1 after being metabolized in the body.

The prodrug of the TRPV1 agonist is not particularly limited as long as it is a compound that exhibits the agonist action of TRPV1 after being metabolized in the body. For example, acetaminophen, phenacetin and the like can be mentioned. Phenacetin is metabolized to acetaminophen in the body, and acetaminophen is hydrolyzed to p-aminophenol by deacetylation, and then arachidonic acid is added by fatty acid amide hydrolase and metabolized to AM404. It has been known.

As shown in Examples described later, AM404, which is an agonist of TRPV1, has a therapeutic effect on tardive dyskinesia, and acetaminophen, which is a prodrug of AM404, has a therapeutic and preventive effect on tardive dyskinesia. The therapeutic effect of acetaminophen on tardive dyskinesia is not confirmed when TRPV1 is deficient. From this, it is considered that the treatment or prevention of tardive dyskinesia is possible by activating TRPV1. Therefore, an agonist of TRPV1 or a prodrug thereof exerts a therapeutic or preventive effect on tardive dyskinesia.

In addition, this disclosure is based on the following general formula (1).

[In the formula, R ¹ represents a hydrogen atom or a lower alkyl group. n represents an integer of 1-4, and when n represents an integer of 2 or more, n pieces of R ¹ may be the same or different. R ² represents an aliphatic hydrocarbon group having 1 to 25 carbon atoms, in which a hydrogen atom may be substituted with a hydroxyl group. X represents an imino (-NH-) group, a methylene group, or an oxygen atom. When a indicates an integer of 1 to 5, and a indicates an integer of 2 or more, a Xs may be the same or different. ]
It also includes a composition containing the compound represented by (1) as an active ingredient. The general formula exemplifies a preferred chemical formula of an agonist of TRPV1 or a prodrug thereof. Hereinafter, the "composition of the present disclosure" also includes a composition containing a compound represented by the general formula (1) as an active ingredient.

The lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, and is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-. Butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl group and the like can be mentioned. Of these, methyl or ethyl is more preferable. The position of OR ¹ may be any of the para-position, the meta-position, and the ortho-position with respect to the carbon atom to which X is bonded, but it is preferably the para-position or the meta-position, which is the para-position. Is more preferable.

N indicates an integer of 1 to 4, and the upper limit or lower limit of the range may be, for example, 2 or 3.

The aliphatic hydrocarbon group having 1 to 25 carbon atoms is a linear or branched saturated or unsaturated aliphatic hydrocarbon group. The hydrogen atom of the aliphatic hydrocarbon group may be substituted with a hydroxyl group. The number of hydroxyl groups substituted varies depending on the number of carbon atoms constituting the aliphatic hydrocarbon group and the like, and examples thereof include 1, 2, or 3.

Examples of the linear or branched saturated aliphatic hydrocarbon group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert. -Pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl , N-Octadecyl, n-Nonadecyl, n-Icosyl, n-Henikosyl, n-docosyl, n-Tricosyl, n-tetracosyl, n-pentacosyl groups, etc., linear or branched alkyl having 1 to 25 carbon atoms. The group is mentioned. The upper or lower limit of the carbon number range is, for example, 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20, It may be 21, 22, 23, or 24.

The linear or branched unsaturated aliphatic hydrocarbon group is a hydrocarbon group having an unsaturated bond (double bond and / or triple bond) in the molecule, and is, for example, the above-mentioned linear or branched unsaturated bond. Among the branched saturated aliphatic hydrocarbon groups, a linear or branched saturated aliphatic hydrocarbon group having 2 or more carbon atoms and having one or more unsaturated bonds can be mentioned. As the unsaturated bond, a double bond is preferable. The upper limit of the number of unsaturated bonds varies depending on the number of carbon atoms constituting the aliphatic hydrocarbon group and the like, but may be, for example, 2, 3, 4, 5, 6 or 7.

Of the aliphatic hydrocarbon group represented by R ^2, particularly preferred examples are as follows.

As shown in the examples below, the aliphatic hydrocarbon group represented by R ² may be a single carbon number, even 19 shows the therapeutic effect of tardive dyskinesia. Therefore, the structure of the aliphatic hydrocarbon group represented by R ² is widely accepted.

A indicates an integer of 1 to 5, and the upper limit or the lower limit of the range may be, for example, 2, 3, or 4. When a is an integer of 2 or more, the oxygen atom does not continue as X.

For example, the following structure can be mentioned. In the structure shown below, a benzene ring is bonded to the left side.
-NH-
-CH _2- NH-
-CH _2- CH _2- NH-
-CH _2- CH _2-
-CH _2- O-

Examples of the compound represented by the general formula (1) include AM404, capsaicin, acetaminophen, phenacetin, orbanyl, arvanyl, gingerol, vanillyl acetone, capsiate, shogaol, N-arachidone dopamine (NADA), N. -Ole oil dopamine (OLDA) and the like can be mentioned. These can be used alone or in combination of two or more. The structures of these compounds are shown in Table 1.

When the compound represented by the general formula (1) is a prodrug of an agonist of TRPV1, in the general formula (1), a is 1 and X is an imino (-NH-) group. More preferred. That is, it is more preferable that the compound is represented by the following general formula (1A).

It is presumed that the TRPV1 agonist prodrug represented by the structure undergoes hydrolysis at the amide bond and is metabolized to a compound exhibiting TRPV1 agonist action.

The number of carbon compound represented by the general formula (1) is, when a prodrug of agonist TRPV1 is constituting the general formula (1A), the aliphatic hydrocarbon group represented by R ^2, For example, it is preferably 1 to 16. The upper or lower limit of the range may be, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

The above-mentioned active ingredient may be a natural product or a synthetic product, and is not particularly limited to a product purified from a natural product or a commercially available product. When the above-mentioned active ingredient is a synthetic product, it can be synthesized by a known method or a method that can be easily conceived from a known method.

The above-mentioned active ingredient may be a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; salts with organic bases such as ammonium salts; hydrochloric acid, phosphoric acid and the like. Salts with inorganic acids; salts with organic acids such as acetic acid, citric acid, succinic acid and the like.

The content of the above-mentioned active ingredient in the composition of the present disclosure is not particularly limited, and can be appropriately set in the range of, for example, 1% by mass to 90% by mass. The upper or lower limit of the range may be, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, or 80% by mass.

The composition of the present disclosure contains the above-mentioned active ingredient, and may further contain other ingredients. Other ingredients include pharmaceutically acceptable bases, carriers, and / or additives (eg, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, lubricants, etc. Agents, antioxidants, preservatives, coating agents, colorants, other agents such as gastric mucosa protective agents) and the like can be exemplified. The form of the composition of the present disclosure is also not particularly limited, and tablets, pills, capsules, powders, fine granules, granules, liquids, troches, jellies, injections, ointments, extracts, suppositories. , Suspension agents, tincture agents, ointments, poultices, nasal drops, inhalants, liniments, lotions, aerosols and the like can be exemplified.

The composition of the present disclosure can be prepared by a conventional method by combining the above-mentioned active ingredient with other ingredients as needed.

The composition of the present disclosure can be used as a pharmaceutical composition.

The administration (ingestion) amount of the composition of the present disclosure is not particularly limited, and is determined by the age, sex, degree of symptoms, intake method, etc. of the subject to be ingested.

Mammals are preferred as the subject to which the compositions of the present disclosure are administered. It may be a non-human mammal as well as a human. Target humans include, for example, humans with or suspected of having tardive dyskinesia, humans who have been taking anti-dopamine drugs for a long period of time, and people who are planning to take anti-dopamine drugs for a long period of time. Can be mentioned.

As an administration method, for example, it can be administered orally and parenterally (for example, vein, artery, muscle, subcutaneous, abdominal cavity, rectum, transdermal, topical, etc.).

Since the composition of the present disclosure contains an agonist of TRPV1 or a prodrug thereof, it can be preferably used for the treatment or prevention of tardive dyskinesia. It is known that acetaminophen, which is a prodrug of AM404, is hydrolyzed to p-aminophenol by deacetylation, and then arachidonic acid is added by fatty acid amide hydrolase and metabolized to AM404. .. Thus, although not bound by theory, for example, TRPV1 agonist prodrugs are hydrolyzed and then metabolized by fatty acid amide hydrolases to compounds that exhibit TRPV1 agonistic activity. Therefore, the composition of the present disclosure can be preferably used for the treatment or prevention of tardive dyskinesia.

The present disclosure also preferably includes a method for screening an active ingredient for treating or preventing tardive dyskinesia, using TRPV1 activation as an index. Hereinafter, the method may be referred to as "the method of the present disclosure". As shown in Examples described later, it is possible to treat or prevent tardive dyskinesia by activating TRPV1, and therefore, according to the method of the present disclosure, activation of TRPV1 (TRPV1 agonist action) is performed. As an index, an active ingredient for treating or preventing tardive dyskinesia can be screened.

The activation of TRPV1 is a known method capable of measuring the activation of TRPV1 by adding a test component to cells expressing TRPV1, such as measuring a change in intracellular calcium concentration or a change in intracellular calcium concentration. Can be measured by.

As a method for screening an active ingredient, a component in which TRPV1 is activated is selected as an active ingredient for treating or preventing tardive dyskinesia when the test ingredient is contained, as compared with the case where the test ingredient is not contained. The test component may be compared with the component having TRPV1 agonist activity (control), and the test component showing the same level of TRPV1 activity as the control is effective for treating or preventing tardive dyskinesia. It may be selected as an ingredient.

In this specification, "includes" also includes "consisting of" and "consisting of" (The term "comprising" includes "consisting essentially of" and "consisting of."). The present disclosure also includes all combinations of the constituent requirements described herein.

Further, the various characteristics (property, structure, function, etc.) described for each embodiment of the present disclosure described above may be combined in any way in specifying the subject matter included in the present disclosure. That is, the present disclosure includes all subjects consisting of any combination of each of the combinable properties described herein.

The contents of the present disclosure will be specifically described with reference to the following examples. However, this disclosure is not limited to these. In the following, unless otherwise specified, the experiments are carried out under atmospheric pressure and normal temperature conditions (for example, 25 ° C.). Also, unless otherwise specified, "%" means "mass%". Further, + in the figure indicates that the component was added, and-indicates that the component was not added.

Test example 1. Prophylactic effect of acetaminophen on tardive dyskinesia Male Wistar rats (9 weeks old) were orally administered 1 mg / kg haloperidol and 50 mg / kg or 100 mg / kg acetaminophen for 21 days. On the 22nd day from the start of administration, the number of VCMs (involuntary masticatory movements: Vacuous chewing movements) per 3 minutes was measured as an experimental index of dyskinesia. The results are shown in FIG. The same measurement was performed on rats not receiving haloperidol or acetaminophen (control) and rats receiving only haloperidol.

As shown in FIG. 1, the number of VCMs was increased by administration of haloperidol. On the other hand, the combined use of haloperidol and acetaminophen significantly reduced the number of VCMs as compared to administration of haloperidol alone. From this result, it was found that acetaminophen has a preventive effect on tardive dyskinesia induced by haloperidol. No effect of administration of acetaminophen on liver function (alanine aminotransferase and aspartate aminotransferase) was observed.

Test example 2. Therapeutic effect of acetaminophen on tardive dyskinesia Male Wistar rats (9 weeks old) were orally administered 1 mg / kg of haloperidol for 21 days. On the 22nd day from the start of administration, 100 mg / kg of acetaminophen was orally administered, and 60 minutes later, the number of VCMs per 3 minutes was measured. The results are shown in FIG. The same measurement was performed on rats not receiving haloperidol or acetaminophen (control), rats receiving only haloperidol, and rats receiving only acetaminophen.

As shown in FIG. 2, administration of haloperidol increased the number of VCMs. On the other hand, when acetaminophen was administered after haloperidol was administered for 21 days, the number of VCMs was significantly reduced as compared with the case where only haloperidol was administered. From this result, it was found that acetaminophen has not only a preventive effect but also a therapeutic effect on tardive dyskinesia induced by haloperidol.

Test example 3. Effect of acetaminophen on the effect of haloperidol on schizophrenia Male Wistar rats (9 weeks old) were orally administered 1 mg / kg haloperidol and 100 mg / kg acetaminophen. After 1 hour, 2 mg / kg of methamphetamine was intraperitoneally administered, and after 15 minutes, the amount of activity per 30 minutes (distance traveled per 30 minutes) was measured as an experimental index of schizophrenia positive symptoms. The results are shown in FIG. The same measurement was performed on rats not administered with haloperidol, acetaminophen or methamphetamine (control), rats administered with only methamphetamine, and rats administered with methamphetamine and haloperidol.

As shown in FIG. 3, the amount of activity increased by the administration of methamphetamine was significantly decreased by the administration of haloperidol. This indicates that administration of haloperidol suppressed schizophrenia-positive symptoms in rats that showed schizophrenia-positive symptoms by administration of methamphetamine. Here, even when acetaminophen was administered together with haloperidol, the effect of reducing the amount of activity (the effect of suppressing positive symptoms of schizophrenia) was maintained, so that acetaminophen was used for schizophrenia of haloperidol. It was found that it did not affect the effect.

Test example 4. Therapeutic effect of AM404 on tardive dyskinesia Male Wistar rats (9 weeks old) were orally administered 1 mg / kg of haloperidol for 21 days. On the 22nd day from the start of administration, 50 nmol of AM404 was intraventricularly administered, and 30 minutes later, the number of VCMs per 3 minutes was measured. The results are shown in FIG. The same measurement was performed on rats not receiving haloperidol or AM404 (control), rats receiving only haloperidol, and rats receiving only AM404.

As shown in FIG. 4, the frequency of VCMs was increased by the administration of haloperidol. On the other hand, when AM404 was administered after 21 days of administration of haloperidol, the number of VCMs was significantly reduced as compared with the case where only haloperidol was administered. From this result, it was found that AM404 has a therapeutic effect on tardive dyskinesia induced by haloperidol as well as acetaminophen.

Test example 5. Effect of TRPV1 on the therapeutic effect of acetaminophen on tardive dyskinesia Male C57BL / 6J wild-type mice and TRPV1 gene-deficient (TRPV1-KO) mice (6-7 weeks old) were given 2 mg / kg of haloperidol. It was orally administered for 21 days. On the 22nd day from the start of administration, 300 mg / kg of acetaminophen was orally administered, and 60 minutes later, the number of VCMs per 3 minutes was measured. The results are shown in FIG. For each of the wild-type mouse and TRPV1-KO mouse, the same measurement was performed for mice not administered with haloperidol or acetaminophen (control), mice administered with only haloperidol, and mice administered with only acetaminophen. It was. TRPV1-KO mice were prepared by the method described in M. J. Caterina et al, Science, 2000, 288, 306-313.

As shown in FIG. 5, the number of VCMs was increased by administration of haloperidol in both wild-type mice and TRPV1-KO mice. In wild-type mice, administration of acetaminophen was found to significantly reduce the number of VCMs compared to administration of haloperidol alone. On the other hand, in TRPV1-KO mice, the number of VCMs did not change even when acetaminophen was administered, as compared with the case where only haloperidol was administered. From this result, it was considered that acetaminophen prevents and / or treats haloperidol-induced tardive dyskinesia via TRPV1.

AM404, which is a metatransformer of acetaminophen and an agonist of TRPV1, has a therapeutic effect on tardive dyskinesia (Fig. 4), and the effect of acetaminophen on tardive dyskinesia in TRPV1-KO mice. (Fig. 5), it was considered that acetaminophen was metabolized to AM404 and activated TPPV1 to show therapeutic and preventive effects on tardive dyskinesia.

Test example 6. Therapeutic effect of orbanil on tardive dyskinesia Male C57BL / 6J wild-type mice were orally administered 2 mg / kg of haloperidol for 21 days. On the 22nd day from the start of administration, Vehicle (5% DMSO, 1% tween80) was administered intracerebrally (dorsolateral striatum) for 4 minutes, and 5 minutes later, the number of VCMs per 5 minutes was measured. After that, 2 mg / kg of haloperidol was orally administered for 4 days, and on the 26th day, 10 ng / unilateral orbanyl was administered to both sides of the brain (dorsolateral striatum) for 4 minutes, and 5 minutes later, VCMs per 5 minutes The number of times was measured (Group1: n = 4). The number of VCMs was measured twice by the same method except that the administration order of Vehicle and Orbanyl was changed (Group2: n = 4). The average value for each treatment obtained from Groups 1 and 2 is shown in FIG. The number of VCMs was also measured for mice treated by the same method except that orbanil was not administered.

As shown in FIG. 6, when orbanil was administered, the number of VCMs was significantly reduced as compared with the case where orbanil was not administered. From this result, it was found that orbanil has a therapeutic effect on tardive dyskinesia induced by haloperidol.

Test example 7. Therapeutic effect of Albanil on tardive dyskinesia The number of VCMs per 5 minutes was measured by the same method as in Test Example 6 except that Albanil was used instead of Orbanil (Group1: n = 3, Group2: n). = 4). The results are shown in FIG.

As shown in FIG. 7, when Albanil was administered, the number of VCMs was significantly reduced as compared with the case where Albanil was not administered. From this result, it was found that Albanil has a therapeutic effect on tardive dyskinesia induced by haloperidol.

Test example 8. Effect of TRPV1 on the therapeutic effect of capsaicin on tardive dyskinesia The number of VCMs per 5 minutes was measured by the same method as in Test Example 6 except that capsaicin was used instead of orbanyl (Group1: n = 3). , Group2: n = 4). In addition, the number of VCMs was similarly measured in TRPV1 gene-deficient (TRPV1-KO) mice (6 to 7 weeks old) instead of male C57BL / 6J wild-type mice. The results are shown in FIG.

As shown in FIG. 8, in wild-type mice, a significant decrease in the number of VCMs was confirmed by administration of capsaicin. On the other hand, in TRPV1-KO mice, the number of VCMs did not change even when capsaicin was administered, as compared with the case where capsaicin was not administered. From this result, it was considered that capsaicin prevents and / or treats haloperidol-induced tardive dyskinesia via TRPV1.

Test example 9. Therapeutic effect of capsaicin on tardive dyskinesia Male Wistar rats (9 weeks old) were orally administered 2 mg / kg of haloperidol for 21 days. On the 22nd day from the start of administration, 5,10 mg / kg of capsaicin was orally administered, and 30 minutes later, the number of VCMs per 3 minutes was measured. The results are shown in FIG. The same measurement was performed on rats that received neither haloperidol nor capsaicin, rats that received only haloperidol, and rats that received only capsaicin.

As shown in FIG. 9, when capsaicin was administered after haloperidol was administered for 21 days, the number of VCMs was reduced as compared with the case where only haloperidol was administered. From this result, it was found that capsaicin has a therapeutic effect on tardive dyskinesia induced by haloperidol.

Test Example 10. Therapeutic effect of phenacetin on tardive dyskinesia Male Wistar rats (9 weeks old) were orally administered 2 mg / kg of haloperidol for 21 days. On the 22nd day from the start of administration, 300 mg / kg of phenacetin was orally administered, and 60 minutes later, the number of VCMs per 3 minutes was measured. The results are shown in FIG. The same measurement was performed on rats that received neither haloperidol nor phenacetin, rats that received only haloperidol, and rats that received only phenacetin.

As shown in FIG. 10, when phenacetin was administered after haloperidol was administered for 21 days, the number of VCMs was reduced as compared with the case where haloperidol alone was administered. From this result, it was found that phenacetin has a therapeutic effect on tardive dyskinesia induced by haloperidol.

Claims (4)

1. A composition for treating or preventing tardive dyskinesia, which comprises an agonist of TRPV1 or a prodrug thereof as an active ingredient.
2. The following general formula (1)
   

   

   [In the formula, R ¹ represents a hydrogen atom or a lower alkyl group. n represents an integer of 1-4, and when n represents an integer of 2 or more, n pieces of R ¹ may be the same or different. R ² represents an aliphatic hydrocarbon group having 1 to 25 carbon atoms, in which a hydrogen atom may be substituted with a hydroxyl group. X represents an imino (-NH-) group, a methylene group, or an oxygen atom. When a indicates an integer of 1 to 5, and a indicates an integer of 2 or more, a Xs may be the same or different. ]
   A composition for treating or preventing tardive dyskinesia, which comprises the compound represented by (1) or a salt thereof as an active ingredient.
3. The composition according to claim 1 or 2, which is for oral administration or intravenous injection.
4. A method for screening an active ingredient for treating or preventing tardive dyskinesia, using the activation of TRPV1 as an index.

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