WO2006013833A1 - Novel anxiolytic agent - Google Patents

Abstract

An anxiolytic agent characterized by containing as an active ingredient 4-(1-piperidylmethyl)phenol (PMP) or a derivative having the same biological activity as that thereof; and a method of using as an anxiolytic agent PMP or a derivative having the same biological activity as that thereof. The PMP is an anxiolytic agent capable of acting via sigma receptor, having the advantage that it even in a small amount is effective and is capable of oral administration. The PMP has the potential for becoming an excellent medicinal drug for treating anxiety disorders.

Description

 Specification

 New anti-anxiety agent

 Technical field

 [0001] The present invention relates to an anxiolytic agent characterized by containing 4- (1-piperidylmethyl) phenol or a derivative having a biological activity equivalent thereto as an active ingredient. The present invention further relates to a method of using 4- (1-piperidylmethyl) phenol or a derivative having biological activity equivalent thereto as an anxiolytic agent.

 Background art

 [0002] Currently, more than 490 million people in the world are said to have anxiety! /, Or have a tendency to have anxiety or anxiety. And the number of people with anxiety is on the rise, and the market for drugs to treat anxiety, or anti-anxiety drugs, will continue to grow at an annual rate of 8.0% until 2007. It has been broken.

 [0003] The main anti-anxiety agents currently on the market as pharmaceuticals are benzodiazepine derivatives. Benzodiazepine-based anxiolytics are classified into long-term, intermediate, and short-term types based on the duration of action associated with metabolic rate. Long-term representative drugs include chlordiazepoxide, diazepam, metazebam, prazepam, chlorazepate, cloxazolamoxaxazolam. Intermediate type representative drugs include oxazepam, and short-time representative drugs include triazolam, bromazepam, fluzazepam and lorazepam.

 [0004] Other than benzodiazepine derivatives, chenodiazepine derivatives, strong rubamate derivatives, diphenylmethane derivatives and the like are also used as anxiolytic agents. Representative drugs of chenodiazepine derivatives include clothiazepam and etizolam, representative drugs of strength rubamate derivatives include mepronomate, and diphenylmethane derivatives include hydroxyzine. Currently used anti-anxiety agents are described in various pharmacology textbooks, and examples include “New Pharmacology” by Chikako Tanaka and Takashi Kato, edited by Nanedo.

[0005] These anxiolytics of benzodiazepine derivatives have excellent safety properties. It has a pharmacological action such as anticonvulsant action, muscle relaxation action, sedative hypnosis action and anesthetic enhancement action at the same time. Therefore, in addition to benzodiazepine derivatives, there is still a demand for an anxiolytic agent that is mild and highly safe and can be easily taken orally.

 [0006] By the way, the sigma (sigma) receptor is a receptor found as a receptor for drugs such as SKF10,047 and 1,3-di-0-tolyguanidine (DTG). The sigma receptors are independent of opioid receptors because the forces μ, δ, and κ receptors that were originally classified as opioid receptors are blocked by naloxone in common, but only σ receptors are not blocked. It has come to be considered a receptacle.

 [0007] Further studies have shown that there are two subtypes of sigma receptors, sigma-1 and sigma-2, and their pharmaceutical profile, function and molecular size have been identified. The sigma 1 receptor was cleaved, and the results revealed that it had only one transmembrane domain.

 [0008] Neuropeptide Y is an endogenous substance that exhibits a weak affinity for sigma receptors, and corticosterone, dehydroepandrosterone (DHEA), etc. have been reported as non-peptides. The true endogenous ligand and second messenger are still unknown.

 [0009] In vivo effects of sigma receptors are known to antagonize opioid analgesia, to have anti-anxiety and anti-amnestic effects, and to suppress self-issued movement, and anti-schizophrenia It has been made a viewpoint as a medicine. Attempts to develop therapeutic agents for schizophrenia that act via sigma receptor antagonists are reported, for example, in a review by Okuyama et al. (Shigeru Okuyama, Journal of Japanese Pharmacology (1999) 114 p3-11) .

[0010] Not only that, sigma receptors are involved in a variety of physiological functions, and the ligands of sigma receptors are glucose utilization, neuroprotective action, antipsychotic action, antidepressant action, anti-unsafe action, Dementia, anticonvulsant, drug-dependent antagonism, antitussive, antitussive, anti-inflammatory, tear protein release, and central urinary reflex suppression. Therefore, not only the above-mentioned schizophrenia treatments but also sigma receptor ligands have been developed as drugs for various diseases! A review by Nabeshima et al. (Toshitaka Nabeshima, Japanese Pharmacology Reported in a magazine (1999) 114 pl3-23).

[0011] There are many other reviews describing sigma receptors. As an example of such literature, a review of drugs that act on sigma receptors is given by a review by Rufujita (Michiya Fujita, Biological Chemistry (1991) 42 p395-397) and a review by Livio Brasili et al. Livio Brasili, P harmceutica Acta Helvctiae, (2000): 74, p201-203) and Wayne DB et al. (Wayne DB, Pharmceutica Acta Helvctiae, (20 00): 74 , p211-228).

 Brief Description of the Invention

 [0012] From the knowledge about the function of sigma receptor, the present inventors can focus on the receptor and find a new ligand of sigma receptor to obtain a new anxiolytic agent. I thought. Therefore, an object of the present invention is to provide a novel anxiolytic agent that acts via a sigma receptor.

 [0013] As a result of intensive studies by the present inventors, 4- (1-piperidylmethyl) phenol (4- (l-pip erydylmethyl) phenol: hereinafter abbreviated as PMP) is a sigma receptor, particularly sigma-1 It was found to have affinity for the receptor. Furthermore, when the pharmacological action of PMP was further examined, it was found that it exhibits an anxiolytic action in mice. The anxiolytic effect of PMP appeared at low doses and was effective after oral administration. Although PMP itself is a known substance, there have been no examples of anti-anxiety activity reported so far.

[0014] It should be noted that PMP selectively binds to sigma-1 receptor among sigma receptors, and therefore the action of PMP is expressed through sigma-1 receptor. Data indicating this will be described in detail in the following examples. PMP sigma - 1 selectivity for the receptor even in the presence of PMP in Kogu 10- ⁴ molar concentration, dopamine D1 receptor, dopamine D2 receptor, the histamine HI receptor, histamine H2 receptor, serotonin receptor There is also an in vitro binding assay finding that it does not substantially affect the binding of their ligands to. The terms “sigma receptor”, “sigma-1 receptor”, and “sigma-2 receptor” in the present specification should be interpreted as meanings commonly used in this technical field. is there. Thus, those skilled in the art, for example, reviewed Walker et al. (Walker JM et al (1990): 42, p355-402) and Okuyama et al. (Toshitaka Nabeshima, Shigeru Okuyama, Journal of Japanese Neuropsychopharmacology (1994): 14, p51-76) The concept of “sigma receptor” and its subtypes “sigma-1 receptor” and “sigma-2 receptor” in the specification of the application can be understood.

[0015] Therefore, the present invention provides an anxiolytic agent characterized by containing 4- (1-piperidylmethyl) phenol (PMP) or a derivative having biological activity equivalent thereto as an active ingredient. is there. Furthermore, the present invention provides a method of using 4- (1-piperidylmethyl) phenol (PMP) or a derivative having biological activity equivalent thereto as an anxiolytic agent.

 [0016] PMP has an anxiolytic action via a sigma receptor. Therefore, according to the present invention, an anxiolytic agent characterized by containing PMP or a derivative having a biological activity equivalent thereto as an active ingredient, and a derivative having a biological activity equivalent to PMP or an equivalent agent. Given how to use. Since PMP according to the present invention is effective at a low dose and can be administered orally, it may be an excellent drug for treating anxiety. It is also possible to search for anxiolytic effects using PMP as a lead compound.

 Brief Description of Drawings

 [0017] FIG. 1 is a graph showing the results of testing the anxiolytic activity of mice administered intraventricularly with PMP in an elevated plus maze.

 FIG. 2 is a graph showing the results of testing an anxiolytic activity of mice administered orally with PMP in an elevated plus maze.

 FIG. 3 is a graph showing the results of testing the anxiolytic activity of mice administered orally with diazebam in the elevated plus maze.

 FIG. 4 is a graph showing the results of examining the effect of BMY14802 on anxiolytic activity in mice administered with PMP.

 FIG. 5 is a graph showing the results of examining the effects of antisense-oligooxynucleotide and mismatch-oligooxynucleotide on the anxiolytic activity of mice administered with PMP.

 Detailed Description of the Invention

[0018] As described above, the present invention is directed to induction of PMP or equivalent biological activity. An anxiolytic agent characterized by containing the body as an active ingredient and a method of using PMP or a derivative having a biological activity equivalent thereto as an anxiolytic agent are provided. PMP may be a new treatment for anxiety that can replace benzodiazepine derivatives.

 In the present specification, a derivative having a biological activity equivalent to that of PMP means a compound having a partly modified chemical structure of PMP and having an anxiolytic action equivalent to that of PMP. . The term “equivalent” mentioned here means qualitative identity or similarity such as anxiolytic activity, and does not mean quantitative identity or similarity. Examples of such derivatives include compounds represented by any one of the following general formula 1, general formula 2 and general formula 3. In general formula 1, general formula 2, and general formula 3, R, R, R, and R are each independently H (hydrogen), OH (hydroxyl), CH (methyl

 1 2 3 4 3 group), group power consisting of OCH (methoxy group)

 Three

More preferably, the compound represented by general formula 1 is PMP. However, the derivatives having biological activity equivalent to PMP in the present invention are not limited to those compounds, but other derivatives may be used as long as they are derivatives of PMP having biological activity equivalent to PMP. Compounds are also within the scope of the present invention.

General formula 1

一般式 2

General formula 2

Formula 3

[0020] The route of administration of PMP used in the present invention is not particularly limited, and oral administration, parenteral administration, and rectal administration can be used orally or parenterally. PMP method dosages of administration, the condition of the patient, varies depending on the age or the like, in the case of oral administration, usually _{0.1 μ § / 1¾~1000 / ζ g} / kg per day, preferably 1 mu g / kg to 100 g / kg. PMP is usually administered in the form of a preparation prepared by mixing with a pharmaceutically acceptable pharmaceutical carrier. Used as such carriers are substances that are commonly used in the pharmaceutical field and do not react with PMP. In the case of parenteral administration with an injection, it can be administered by various means such as intraventricular injection, intravenous injection, intramuscular injection, subcutaneous injection, and intradermal injection.

[0021] Specifically, examples of substances that can be used as such carriers include lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium metasilicate aluminate, synthetic aluminum silicate, carboxymethylcellulose. Sodium, hydroxy Mouth pill starch, carboxymethylcellulose calcium, ion-exchange rosin, methylcellulose, gelatin, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, polybulurpyrrolidone, polybulur alcohol, light anhydrous carboxylic acid, magnesium stearate, talc, tragacanth, Bentonite, bee gum, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, refined lanolin, glyce gelatin, polysorbate, macrogol, vegetable oil, wax, liquid paraffin, white petrolatum, fluorocarbon, nonionic interface Activators, propylene alcohol, water and the like.

 [0022] The dosage form to be administered is not particularly limited. The possible dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels. , Patches, inhalants, injections and the like. These preparations are prepared according to a conventional method. The liquid preparation may be dissolved or suspended in water or other appropriate solvent at the time of use. Tablets and granules may be coated by a known method. In the case of an injection, it is prepared by dissolving PMP in water, but if necessary, it may be dissolved in physiological saline or glucose solution, and a buffer or preservative may be added.

 [0023] These preparations may contain PMP in a proportion of 0.01% to 100% by weight, preferably 1 to 90% by weight. These formulations may also contain other therapeutically valuable ingredients.

[0024] In order to produce a solid preparation for oral administration, the active ingredient and excipient components such as lactose, starch, crystalline cellulose, calcium lactate, anhydrous caustic acid, etc. are mixed into a powder, and further, If necessary, add a binder such as sucrose, hydroxypropylcellulose, or polybulurpyrrolidone, a disintegrant such as carboxymethylcellulose or carboxymethylcellulose calcium, and wet or dry granulate to form granules. In order to produce tablets, these powders and granules can be tableted as they are or with the addition of lubricants such as magnesium stearate and talc. These granules or tablets are coated with an enteric solvent base such as hydroxypropyl methylcellulose phthalate or methyl methacrylate polymer and coated with an enteric solvent preparation, or with ethyl cellulose, carnauba wax, hardened oil, etc. It can also be made into a pharmaceutical preparation. To produce capsules, add powder or granules. Strength for filling hard capsules The active ingredient can be coated as it is or dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc., and then coated with a gelatin film to make soft capsules.

 [0025] In order to produce a liquid preparation for oral administration, an active ingredient and a sweetener such as sucrose, sorbitol and glycerin are dissolved in water, and a transparent syrup, further essential oil, ethanol and the like are added to form an elixir. It can also be used as an emulsion or suspension by adding coconut, gum arabic, tragacanth, polysorbate 80, sodium carboxymethylcellulose, etc. These liquid preparations may contain a corrigent, a coloring agent, a preservative and the like as desired.

[0026] In order to produce an injection, the active ingredient is adjusted to a pH adjusting agent such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate as necessary. Dissolve in distilled water for injection together with isotonic agents such as sodium and glucose, add aseptic filtration to fill ampoules, add mannitol, dextrin, cyclodextrin, gelatin, etc. It may be a dissolved injection. In addition, an emulsion for injection can be prepared by emulsifying in water an active ingredient containing reticin, polysorbate 80, polyoxyethylene hydrogenated castor oil and the like.

[0027] In order to produce a rectal dosage form, the active ingredient is moistened with a suppository base material such as cacao butter, fatty acid tri-, di- and monoglycerides, polyethylene glycol, etc., dissolved, poured into a mold, and cooled. The active ingredient may be dissolved in polyethylene glycol, soybean oil, etc. and then covered with a gelatin film.

 [0028] In order to produce an external preparation for skin, the active ingredient is mixed with white petrolatum, beeswax, liquid paraffin, polyethylene glycol, etc., and if necessary, moisturized and kneaded to form an ointment, mouth gin, acrylic After kneading with a pressure-sensitive adhesive such as an acid alkyl ester polymer, it is spread on a non-woven fabric such as polyalkyl to form a tape.

[0029] As shown in the Examples below, PMP was shown to have an anxiolytic effect on mice. However, in the present invention, animals to which PMP is administered are not limited to mice, but a wide range of animals including rodents, non-human primates, animals raised as pets, animals raised as livestock In contrast, PMP can be administered as an anxiolytic agent. Preferred examples of such animals include mice, rats, Guinea pigs; non-human primates such as monkeys, chimpanzees, gorillas; animals raised as pets include dogs, cats; animals raised as domestic animals include horsetails, horses, eagle birds, and hidges Yes, but not limited to those animals. As used herein, the term “animal” is intended to exclude humans. However, PMP can be administered to human anxiety patients to treat anxiety, and the mode of administering PMP to humans is also within the scope of the present invention.

 [0030] Based on the knowledge of having PMP anxiolytic activity, it is also possible to screen for sigma receptor binding activity of peripheral compounds using PMP as a lead compound to obtain further anxiolytic agents. . More specifically, for example, a compound designed based on PMP is examined for its ability to bind to a sigma receptor using a receptor binding assay, and a compound that binds to the sigma receptor is screened. The compound thus selected is administered to an animal such as a mouse, and the anxiolytic activity of the compound is evaluated, for example, in an elevated plus maze experiment described in the following Examples. It is possible to develop an anxiolytic agent completely different from the benzodiazepine derivative by further testing the efficacy and safety of the compound having anxiolytic activity.

 [0031] It should be noted that sigma receptor activity is required by administering an effective amount of a compound represented by any one of the following general formula 1, general formula 2 and general formula 3 to a subject. Methods for activating sigma receptors in the subject are also within the scope of the present invention. The compounds represented by the following general formula 1, general formula 2, and general formula 3 are preferably R, R, R, and R.

 1 2 3 4 Independently H, OH, CH, OCH forces Group force Selected group, more preferably P

 3 3

MP. Here, a subject requiring sigma receptor activity requires, for example, sigma receptor activity in order to ameliorate a disorder of a disease or pathological condition involving sigma receptor activity. A subject that is a subject to whom an effective amount of a compound represented by any one of general formula 1, general formula 2 and general formula 3 is administered. General formula 1

一般式 2

General formula 2

Formula 3

Further, by administering an effective amount of any one compound of general formula 1, general formula 2 and general formula 3 to the subject, the subject having a disease or pathological condition involving sigma receptor activity. Methods of treating are also within the scope of the present invention. In the compounds represented by the following general formula 1, general formula 2, and general formula 3, preferably R, R, R, and R are each independently H, 0H,

 1 2 3 4

 A group selected from the group consisting of CH and 0CH, more preferably PMP. sigma

3 3

A subject having a disease or pathological condition involving receptor activity is suffering from a disease or pathological condition involving abnormal sigma receptor activity, such as anxiety, for example. It means an organism which is a subject to which an effective amount of a compound represented by any one of general formula 2 and general formula 3 is administered. General formula 1

一般式 2

General formula 2

Formula 3

 Example

 [0033] Next, the present invention will be described more specifically with reference to actual examples. However, the following examples do not limit the scope of the present invention.

 [0034] (Synthesis of PMP)

 PMP was synthesized according to the method described by P. Jacob et al. In J. Chromatogr. B, 1995, 664, 449-457. Piperidine (1.7 g, 20 mmol) and p-hydroxybenzaldehyde (1.22 g, 10 mmol) were dissolved in 48 ml of methanol. Add acetic acid to adjust pH to 6.0, NaBH C

 Three

The reaction was initiated by adding N (471.3 mg, 7.5 mmol). The mixture was stirred at room temperature for 70 hours. Methanol was evaporated, and the remaining oil was dissolved in 30 ml of water and acidified to pH 1.0 with diluted HC1.

[0035] The solution was extracted with 20 ml of ethyl acetate and the aqueous layer was made alkaline with ammonia. A precipitate was formed. After centrifugation at 3000 g for 5 minutes, the precipitate was separated, redissolved in diluted HC1, and extracted twice with ethyl acetate. The precipitate was separated by making the aqueous layer alkaline. The final precipitate was purified by HPLC on a 5PE-MS column and separated at a flow rate of 3 ml / min with a linear acetonitrile gradient (0-60% / 30 min) containing 0.1% TFA. Purified PMP was analyzed by LC-Mass.

 [0036] (Receptor binding activity)

Non-selective sigma receptor binding was performed using the method of Weber E et al. (Weber E et al., Proc. Natl. Acad Sci USA, 1986) using [ ³ H] -DTG as a radioligand and by guinea pig brain. ; 83 (22): 8784-8788). Sigma-1 binding was performed using [] -haloperidol as a radioligand with membranes also prepared with human Jurkat cell force (Ganapathy ME et al., J. Pharmacol. Exp. Ther 1999; 289 ( 1): 251-260). Sigma-2 binding was performed using [] -ifenprodil as a radioligand by membranes that were also prepared with rat brain force (Hashimoto K et al., Eur. J. Pharmacol. 5-12-1993). 236 (1) 159-163).

 [0037] (Elevated cross maze experiment)

 The elevated plus maze (EPM) consists of two open arms (24x5x0.5) and two closed arms (24x5x13), which are connected to a central platform that is 50cm above the floor. . Despite being in a high position, the mouse can safely walk because there is an enclosure around the close arm. On the other hand, because the surroundings of the open arm are open and surrounded, the mouse walking on the open arm feels anxiety that the high position force falls. Therefore, the more anxiety the mouse is in the open arm and the more times the mouse enters the open arm, the less the anxiety of the mouse, which becomes an index of anti-anxiety activity.

 [0038] The test was started by placing a mouse on a central platform facing one of the open arms. The cumulative time spent in the open arm, the number of times that it entered the open arm, and the number of times it entered the closed arm during the 5 minute test time were recorded. The percentage of time spent in the open arm and the percentage of entry into the open arm are calculated as indicators of anxiety, and the total number of ingresses indicates mobile activity.

[0039] PMP dissolved in saline solution was placed on the elevated plus maze 10 minutes before the ventricle The ability to be administered by internal (icv) injection was administered by oral route 30 minutes before the elevated plus maze test. Sigma-1 Antagost BMY14802 was given by subcutaneous (sc) injection at 0.5 mg / kg, 10 minutes prior to PMP administration. Antisense-oligodeoxynucleotide (5, -GA GTGCCCAGCCACAACCAGG-3,) and mismatch-oligodeoxynucleotide (5, -GA GGTCCCGACCACACACAGG-3,) (Maurice T et al, Brain Res. 2001; 898 (1 ): 113-121) was dissolved in sterile saline prior to the experiment. On the 1st, 3rd and 5th day, the dose was 10 g / 4 1 / mouse once a day by the intraventricular (icv) route. Injections were alternately performed on the left and right sides of the mouse brain. The elevated plus maze test was performed 24 hours (day 6) after the final oligonucleotide injection.

[0040] (Statistical analysis)

 The data for which the elevated plus maze test ability has increased are expressed as the mean and SEM. Data were analyzed by one-way or two-way ANOVA, followed by Dunnett's test for multiple comparisons. The value of significant difference was set to 0.05.

[0041] (Result)

 PMP showed a relatively high affinity for the sigma receptor. The non-selective binding assembly IC was 200 nM. The IC for sigma-1 binding is 791nM and the sigma-2 binding I

 50 50

 C was 12 mM. So the selectivity of Sigma-1 over Sigma-2 was about 15 times

50

[0042] Fig. 1 shows the results of testing the anxiolytic activity after intraventricular (i.c.v) administration of PMP to mice in the elevated plus maze. n = 9-12, * represents P <0.05, and ** represents P <0.01. Figure 1A is the percentage of time spent in the open arm, Figure 1B is the percentage that entered the open arm, and Figure 1C is the sum that entered the open and closed arms. PMP dose-dependent time spent in the open arm was prolonged (Figure 1A) and entry into the open arm increased (Figure 1B). On the other hand, the total number of ingresses did not change significantly (Fig. 1C). This result indicates that the administered PMP caused anxiety-reducing effects without affecting mobility. The minimum effective dose was lOpmol per mouse.

[0043] Fig. 2 shows the results of testing the anxiolytic activity after oral administration of PMP to mice in the elevated plus maze. n = 10-15, * represents P <0.05, ** represents P <0.01, *** represents P <0.001 . When administered orally, PMP also increased the time and number of entries in the open arm (Figures 2A and B), and did not significantly change the total number of entries (Figure 2C). This suggests that an anxiolytic effect can be obtained by oral administration. The minimum effective dose was 5 μg / kg.

 [0044] Further, as a positive control, the anxiolytic activity after oral administration of diazebam, which is widely used as a benzodiazepine drug, was tested in the elevated plus maze, and the results are shown in FIG. n = 7 and * represents P 0.05. When diazepam was administered orally, the time spent in the open arm and the number of intrusions increased at doses of lmg / kg and 2 mg / kg (Figures 3A and 3B). For jazepam lmg / kg, there was a significant difference between the time spent in the open arm and the number of entries with a probability of 0.05. Based on this result, it was found that the anti-anxiety activity of diazebam, an anti-anxiety drug, was successfully detected in this experimental system. Therefore, it was confirmed from the experimental results of the positive control Jazebam that the experimental system used in this example is reliable.

 [0045] To test whether the anxiolytic effect of PMP is mediated by the sigma-1 receptor, the effect of BMY14802, an antagonist of sigma-1, was tested. Figure 3 shows the anxiolytic effects of PMP (10 nmol / mouse: intracerebral administration) with and without pretreatment with BMY14802 (0.5 mg / kg). n = 14-16, * represents P <0.05, ** represents P <0.01, *** represents P <0.001. • 5 mg / kg BMY14802 had no significant effect on anxiety. However, when pretreated by an antagonist, the migration activity did not change (Figure 4C), but both the percentage of time in the open arm and the percentage of entry decreased to the basal level (Figures 4A and B). This shows that BMY14802, the sigma-1 antagonist, is blocking the anxiety-reducing effect of PMP.

[0046] Next, an attempt was made to knockdown the sigma-1 receptor by antisense pretreatment. Figure 5 shows the results. n = 8-ll. In comparison with the control, * represents P <0.05, ** represents P <0.01, and *** represents P <0.001. In comparison with the antisense-oligooxynucleotide-untreated and PMP-treated groups, # indicates 1 ³ <0.05. Pretreatment with antisense-oligooxynucleotides (denoted as aODN in Fig. 5) itself had no significant effect on anxiety compared to the control group. However, antisense-oligode Pretreatment with oxynucleotides (10 μg / 4 μ 1 / mouse: intracerebroventricular administration) resulted in acupuncture (lOnmol / mouse: intracerebroventricular administration) in both time percent and ingress percentage in the orb arm. The effect was reduced (Figure 5A, B).

 [0047] In addition to the fact that mobility did not change significantly in this experiment (Figure 5C), PMP anxiety was observed when knockdown of the sigma-1 receptor by pretreatment with antisense-oligooxynucleotides. It is clear that the mitigation effect is hindered. The mismatch-oligodeoxynucleotide used as a control (denoted as mODN in Fig. 5) does not affect the anxiolytic activity of PMP (Fig. 5A, B), and the anxiolytic activity of PMP is sigma-1 receptor It shows that it is specifically mediated by

 [0048] The following findings were shown by the above examples. (1) PMP showed relatively high affinity for sigma receptors. (2) BMY14802, a sigma-1 antagonist, inhibited the anxiolytic effect of PMP. (3) The anxiolytic effect of PMP disappeared by pretreatment with Sigma-1 antisense. These three findings suggest that the anxiolytic effect of PMP is mediated by the sigma-1 receptor.

 [0049] The anxiolytic effect of PMP occurred not only by administration to the central nerve but also by oral administration. Since PMP has a low molecular weight and an amphiphilic structure, PMP may be absorbed and transferred through the blood-brain barrier. The effect of PMP was quite strong, and it was effective at lOpmolZ mice for intraventricular administration and 5 / z g / kg for oral administration. Therefore, it is considered that PMP can be a highly effective anxiolytic agent. In order to obtain an anxiolytic effect by oral administration of positive concomitant and diazebam, a role, a concentration of the order of mg / kg was required. Considering this, the anxiolytic effect of PMP, which is effective at low doses, can be said to be quite strong.

 Industrial applicability

[0050] PMP has an anxiolytic action via a sigma receptor, and has an advantage that it is effective at a low dose and can be administered orally. Therefore, the PMP of the present invention has the potential to be an excellent drug for treating anxiety. Furthermore, the present invention has opened the way to search for a superior anxiolytic action using PMP as a lead compound.

Claims

The scope of the claims  [1] An anxiolytic agent comprising 4- (1-piperidylmethyl) phenol or a derivative having biological activity equivalent thereto as an active ingredient.  [2] The derivative having biological activity equivalent to 4- (1-piperidylmethyl) phenol is a compound represented by any one of the following general formula 1, general formula 2 and general formula 3. In the general formula 1, general formula 2, and general formula 3, R, R, R, and R are independently H, 0H  1 2 3 4  , CH, 0CH force, group force, selected group, 3 3  Anxiety agent. General formula 1

—Formula 2 Formula 3

[3] The anxiolytic agent according to claim 2, wherein the compound represented by the general formula 1 is 4- (1-piperidylmethyl) phenol. [4] 0.1 mu is effective by oral administration of a dose of _{§ / 1¾~1000 / ζ g / kg} , according to claim 3 anxiolytic according Agent.  [5] The anxiolytic agent according to claim 4, which is effective by oral administration at a dose of 1 μg / kg to 100 μg / kg. [6] Any one of claims 1 to 3, characterized by acting via a sigma receptor An anxiolytic agent according to one claim. 7. The anxiolytic agent according to claim 6, wherein the sigma receptor is a sigma-1 receptor. [8] The anxiolytic agent according to any one of claims 1 to 3, which is effective by oral administration.  [9] Any one of claims 1 to 3 A pharmaceutical comprising the antianxiety agent according to one claim as an active ingredient.  [10] In a dosage form selected from the group consisting of tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, inhalants and injections. A pharmaceutical product according to claim 9.  [11] The pharmaceutical product according to claim 9, which is a solid preparation or liquid preparation for oral administration.  [12] An anxiolytic agent obtained by using 4- (1-piperidylmethyl) phenol as a lead compound.  [13] A method of using 4- (1-piperidylmethyl) phenol or a derivative having biological activity equivalent thereto as an anxiolytic agent. [14] A method for alleviating anxiety in an animal by administering 4- (1-piperidylmethyl) phenol or a derivative having a biological activity equivalent thereto to the animal. 15. The method according to claim 14, wherein the animal is a rodent, a non-human primate, an animal raised as a pet, or an animal raised as a domestic animal. [16] The animal is a mouse, rat, guinea pig, monkey, chimpanzee, gorilla, inu, cat, ushi 15. The method of claim 14, wherein the animal is also selected for a group power that is also a horse, a horse, a bird, a hedge power. [17] A method for activating a sigma receptor in a subject that requires a sigma receptor activity, and includes any one of the following general formula 1, general formula 2, and general formula 3 In the general formula 1, general formula 2, and general formula 3, R, R, R, and R are each independently H, OH, CH. , OCH group  1 2 3 4 3 3 A process selected from the group consisting of General formula 1

General formula 2 Formula 3

[18] The method according to claim 17, wherein the compound represented by the general formula 1 is 4- (1-piperidylmethyl) phenol.  [19] A method for treating a subject having a disease or pathological condition involving sigma receptor activity, the compound comprising any one of general formula 1, general formula 2 and general formula 3 Wherein R, R, R, R are each independently a group selected from the group consisting of H, OH, CH, and 0CH. 1 2 3 4 3 3 Said method, characterized in that it is. General formula 1

General formula 2

Formula 3

20. The method according to claim 19, wherein the compound represented by the general formula 1 is 4- (1-piperidylmethyl) phenol.