JP2002154956A - Medicament for promoting release of intracerebral dopamine and serotonin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicament especially effective for treating the following diseases or disorders: anxiety including general anxiety disorder, obsessive- compulsive disorder, social anxiety disorder, panic disorder and posttraumatic stress disorder, depression including vascular depression and major depression, schizophrenia including social withdrawal, and schizosis including emotional impuberism. SOLUTION: This medicament or pharmaceutical composition for promoting the release of intracerebral dopamine and serotonin comprises N-anisoyl-γ- aminobutyric acid or p-anisic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to dopamine (D
A) and the use of N-anisoyl-γ-aminobutyric acid (N-anisoyl-GABA) or p-anisic acid as a pharmaceutical composition for promoting serotonin (5-HT) release. In particular, the present invention relates to anxiety disorders, namely generalized anxiety disorder (GAD), obsessive compulsive disorder (OCD), social anxiety disorder (SAD), panic disorder (PD) and post-traumatic stress disorder (PTSD) Depressive, ie cerebral vascular depression and major depression (m
adol depression), etc .; schizophrenia, ie social withdrawal, etc .; and pharmaceutical compositions for autism, eg, emotional immaturity.

[0002]

2. Description of the Prior Art DA and 5-HT are well known as important classical neurotransmitters. Ventral tegmental area (VT
A) Dopaminergic midbrain-cortical limbic pathway from (me)
The socorticolimbic dopaminergic pathway is thought to control movement, reward and motivation, and cognition [Brain Research, 434, 117-165 (1987); Physiolog
ical Review, 71, 155-234 (1991)]. On the other hand, the central serotonergic pathway derived from the raphe nucleus is involved in the regulation of emotion and mood, sleep and wakefulness, appetite, movement, body temperature and cognition through its many receptor subtypes (Annual
s New York Academy of Science, 600, 9-35 (1990); P
harmacology Biochemistry and Behavior, 54,129-141
(1996)]. These dopaminergic and serotonergic pathways are involved in stress adaptation processes and stress-induced diseases [Pharmacology Biochemistry and Behavio
r, 54, 129-141 (1996); Psychopharmacology, 128, 33
1-342 (1996)], for example, GAD, OCD, SAD, PD
And PTSD [Expert Opinion on Investigational Dr.
ugs, 8, 1589-1598 (1999)), and cerebrovascular depression and major depression (Psychosomatics, 41, 5-14 (2000); M
olecular Psychiatry, 5, 14-21 (2000)]. In addition, these nervous systems are also closely linked to autism (Synapse, 6, 292-308 (1990);
Current Opinion Pediatrics, 8, 348-354 (1996)].

[0003] 1-p-Anisoyl-2-pyrrolidinone (aniracetam, EP 5143 and 440)
No. 88) is a mental function activator and has been used for the treatment of emotional disorders (anxiety / irritability and depressed mood) which appear as sequelae after cerebral infarction [IgakuNo Ayumi, 156, No. 2, 1].
43-187 (1991)]. We have previously suggested that this drug interacts with the central monoaminergic nervous system (European Journal of Pharmacology, 342, 127-138).
(1998); Naunyn-Schmiedeberg's Archives of Pharmac
361, 521-528 (2000)] suggests that orally administered aniracetam really activates DA and 5-HT neurotransmission, and which substances, including its metabolites, are actually monoaminergic neurons. It was unknown whether to activate. In addition, the biological activities of N-anisoyl-GABA and p-anisic acid, the major in vivo metabolites of aniracetam, have not been fully elucidated.

[0004]

Many of the obstacles described above are:
Treated primarily by serotonergic drugs such as tricyclic antidepressants, atypical antidepressants, monoamine oxidase inhibitors, 5- _HT1A receptor agonists, and selective 5-HT reuptake inhibitors I have. However, by prescribing these drugs, cardiotoxicity, anticholinergic toxicity, sedation,
Unexpected side effects, such as sleep and sexual disorders, often occur. Thus, the problem solved by the present invention is to provide promising compounds that can safely regulate DA and 5-HT levels in the brain.

[0005] Now, N-anisoyl-GABA or p-
Anisic acid was surprisingly found to enhance DA and 5-HT release in the brain.

[0006]

SUMMARY OF THE INVENTION Accordingly, the present invention provides
It relates to the use of N-anisoyl-GABA or p-anisic acid, preferably in the form of a pharmaceutical composition, for promoting the release of DA and 5-HT in the brain of mammals, preferably humans. These compounds and pharmaceutical compositions include anxiety disorders, such as GAD, OCD, SAD, PD and PTSD; depressive disorders, such as cerebral vascular depression and major depression; schizophrenia, ie, social withdrawal; It is particularly useful for treating autism, ie, emotional immaturity.

[0007] The present invention relates to a pharmaceutical composition for promoting the release of DA and 5-HT in the brain for treating the above-mentioned diseases, which comprises N-anisoyl-GABA or p-anisic acid as an active ingredient.

[0008] The present invention is also intended to promote the release of DA and 5-HT in the brain, especially for anxiety disorders, namely GAD, OC.
D, SAD, PD and PTSD etc .; Depression, such as cerebrovascular and major depression; Schizophrenia,
N-Anisoyl-GA for the treatment of autism, i.e. emotional immaturity, etc.
It also relates to a method using BA or p-anisic acid.

The present invention will be described in detail below. The following description and examples serve to assist the understanding of the invention, but should not be construed as limiting the invention in any manner. The results obtained in the examples are described in the accompanying figures. A brief description of these figures follows. FIG. 1: Effect of systemic administration of aniracetam on DA and 5-HT release in the prefrontal cortex of SHRSP in free movement. The basal release of DA and 5-HT were 3.55 ± 0.42 pmol / 20 min (n = 21) and 2.
53 ± 0.25 pmol / 20 minutes (n = 18). Data are mean ± SEM. E. FIG. M. Represents * Is P <0.05 and ** is P <
0.01. Figure 2: Effect of local perfusion of aniracetam and its metabolites into the ventral tegmental area (A) or prefrontal cortex (B) on DA and 5-HT release in the prefrontal cortex of SHRSP during free movement. . Compounds were perfused for 20 minutes. Data (AUC ₁₈₀ ) calculated from the area under the curve 180 minutes after the start of compound perfusion is the mean ± SEM. E. FIG.
M. Represents * Indicates P <0.
05, ** indicates P <0.01. FIG. 3: Effects of various combinations of aniracetam metabolites alone or two metabolites on immobility time in a forced swimming test using aged rats. Compounds at the indicated dose (mg / kg)
Was orally administered. Data are mean ± SEM. E. FIG. M. (N = 7 to 10 / group). * Vs. vehicle control group
Is P <0.05.

[0010] Both N-anisoyl-GABA and p-anisic acid are known chemical compounds. N-Anisoyl-GABA or p-anisic acid can be synthesized by the method described in Spanish Patent Publication No. 84-538772. p-anisic acid is available from Journal of American
Chemical Society 78, 907-909 (1956).
(St. Louis, USA), Lancaster Synthesis Ltd.
(Lancashire, UK), Wako Pure Chemical Industries (Osaka, Japan)
You can also purchase from.

N-Anisoyl-GABA or anisic acid can be used as a pharmaceutically acceptable formulation. The formulations can be in the form of tablets, coated tablets, dragees, hard gelatin capsules, soft gelatin capsules, solutions, emulsions, or suspensions. The resulting formulation can be administered orally. In addition, the formulation
A suppository for rectal administration or an injection form for parenteral administration may be used.

In the case of oral solid preparations such as tablets, coated tablets, dragees or hard gelatin capsules, N-anisoyl-GABA or p-anisic acid may contain lactose, corn starch and its derivatives, talc, stearic acid and It can be formulated with pharmaceutically inert, inorganic or organic carriers such as bases or salts thereof.

When producing soft or hard gelatin capsules, carriers such as vegetable oils, waxes, fats, oils, gels, semi-solid or liquid polyols and the like can be used as appropriate.

In the production of liquid preparations and syrups, carriers such as water, polyol, sucrose, invert sugar, glucose and the like can be appropriately used.

When preparing an injection, a carrier such as water,
Alcohol, polyol, glycerol, vegetable oil and the like can be used as appropriate.

When preparing suppositories, carriers such as vegetable oils, waxes, oils, gels, and liquid polyols can be used as appropriate. In addition, these formulations include preservatives,
Solvents, stabilizers, wetting agents, emulsifiers, flavorings, bases for changing osmotic pressure, buffers, coatings, and antioxidants,
It can then be used in combination with therapeutically useful compounds.

The route of administration of the above-mentioned preparations is not limited to these, and can be appropriately changed according to the dosage form, the age, sex, symptoms, etc. of the patient.

The administration route, dosage and number of administrations can be appropriately changed according to the age, weight and condition of the patient. In the case of oral administration, the dose is usually 1 to 300 mg / kg (preferably 3 to 30 mg / kg) per adult day, and this dose can be administered in one or several divided doses.

When N-anisoyl-GABA or p-anisic acid was orally administered to rats, acute toxicity (LD
₅₀ value) exceeded 5,000 mg / kg in both genders. After repeated oral administration of this drug to rats for 4 weeks, subacute toxicity such as mortality and abnormalities in hematological, blood biochemical and toxicopathological tests was 60%.
It was not observed up to 0 mg / kg.

[0020]

EXAMPLE Stimulation of DA and 5-HT release by N-anisoyl-GABA or p-anisic acid and anxiety by N-anisoyl-GABA or p-anisic acid, such as GAD, OCD, SAD, PD and PTSD The improvement effect on depression, ie, cerebrovascular depressive state and major depression, etc .; schizophrenia, ie, social withdrawal, etc .; and autism, ie, emotional immaturity, will be specifically described below. Example 1 Test of Stimulating Effect of DA and 5-HT Release Test animals : 13-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were replaced with 1% NaCl instead of water for 5 weeks before the experiment. The solution was given. Test method : SHRSP was anesthetized and a guide cannula was implanted in the prefrontal cortex and VTA. After recovery, insert the concentric microdialysis probe into the guide cannula,
Under free-running conditions, a normal Ringer's solution was perfused at a constant flow rate of 2 μl / min. For oral administration, aniracetam,
Suspended in a 0.25% carboxymethylcellulose solution containing 1-2 drops of Tween 80. For local perfusion, aniracetam and its metabolites are dissolved in Ringer's solution and VTA
Or via a probe inserted into the prefrontal cortex of the cerebral cortex.
Perfused for minutes. Dialysate was collected from the prefrontal cortex of the cerebral cortex every 20 minutes and injected into a high performance liquid chromatography system to quantify extracellular DA and 5-HT concentrations. DA and 5-HT release were expressed as percent change from the mean of three consecutively stable samples before drug administration or perfusion. Test results : Systemic administration of aniracetam promotes DA and 5-HT release in the prefrontal cortex of the cerebral cortex in a dose-dependent manner, with an increase by a high dose of 46% in DA,
It was 41% for 5-HT (FIG. 1). Local perfusion of N-Anisoyl-GABA into VTA significantly enhanced DA release in the prefrontal cortex, but did not affect 5-HT release (FIG. 2A). In addition, p-anisic acid and N-anisoyl-GABA to prefrontal cortex
DA and 5-HT and 5-
HT release was enhanced (FIG. 2B). Therefore, N-
Anisoyl-GABA and p-anisic acid have been suggested to be responsible activators that result in activation of the mid-cortical dopaminergic and serotonergic pathways by aniracetam.

Example 2 Condition Fear Stress Test Animal : Male 6-week-old male ddY mouse Test method : In the training session on day 1, a stainless steel lattice floor (diameter 2 m) surrounded by a wooden soundproof box was used.
The mouse was placed in the center of an electric footshock chamber (24 × 23 × 22 cm) having a length of 1 cm (1 cm interval). A non-evacuable electric footshock (1.0 mA to 0.3 mA) generated by a shock generator / scrambler (SGS-0.02, Muromachi Kikai) through the floor grid of the chamber
) For 10 minutes).
Day 2 Exam Session (Training Session 2)
At 4 hours), the mice were re-entered into the same chamber without foot shock and the freezing time was measured for 6 minutes. A "freezing" mouse is one that has no visible movement of the body or beard except for the respiratory movement and has four legs resting on a floor grid and remaining in a fixed, rigid posture. Compounds were tested on day 2 in oral administration
The parenteral dose was administered 0.5 hours before the test. Bromocriptine was administered 2 hours before the test. Test result : Aniracetam and N-Anisoyl-GABA
The freezing time was significantly shortened by systemic administration of (Table 1). Fluoxetine, a standard compound (selective 5
-HT reuptake inhibitor), 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPA
T, 5-HT _1A receptor agonists) and bromocriptine (DAD ₂ receptor agonists) also significantly reduced freezing time. The anxiolytic effect of aniracetam is N-
Mediated by Anisoyl-GABA.

[0022]

[Table 1]

The data are the average of freezing time ± S.D.
E. FIG. M. Represents * Vs corresponding vehicle control group
Is P <0.05; ** is P <0.01.

Example 3 Elevated plus maze test Animal : 4-week-old male ICR mouse Test method : 50 cm above the floor, two pairs of wallless running paths (open arm, white floor, 25 × 8 cm) ) And two pairs of walled runways (closed arm, black floor with black walls, 25 × 8 × 20 cm) were made of plywood. The mice were placed on the platform (white floor, 8 × 8 cm) in the center of the device, facing either of the open arms. A video camera was used to observe the behavior of the animals, and the number of entries into the open and closed arms and the time spent there were measured for 5 minutes. Entry into the arm was defined as having all four feet in the arm. The compound was tested in Test 1
It was administered orally before time or parenterally 0.5 hours before. Test results : Systemic administration of aniracetam increased the rate of entry into the open arm and increased the time spent there, while p-anisic acid increased the rate of entry (Table 2). Diazepam and nortriptyline (a tricyclic antidepressant) significantly and dose dependently increased both parameters. Tandospirone, a 5-HT _1A receptor agonist, also increased the dwell time rate. The anxiolytic effect of aniracetam was mimicked by p-anisic acid.

[0025]

[Table 2]

The data includes the ratio of the number of times of entry into the open arm and the average ± S.D. Of the stay time ratio in the open arm.
E. FIG. M. Represents * Vs corresponding vehicle control group
Is P <0.05; ** is P <0.01.

Example 4 Social Behavior Test Animal : 6-week-old male ddY mouse Test method : A plastic arena (30 ×) placed in a wooden soundproof box to observe the social behavior of the animal.
20 × 13.5 cm) was used. The light illuminance on the floor of the arena was 380 lux. The mice used as test pairs were group housed in non-adjacent breeding cages.
The experiments were performed under bright color light illumination and without alternating current.
Mice pair members were placed in opposite corners of the arena and subsequently left for 5 minutes. Animal behavior was recorded with a video camera for behavioral assessment. The arena was replaced for each test. Behavioral measures are time and frequency of each non-aggressive, aggressive social behavior (genital smell, neck / tail licking, trunk smell, frontal facing, tracking),
The total and the amount of exercise were performed. Passive physical contact was not considered social behavior. Compounds were administered orally 1 hour before testing or parenterally 0.5 hours before testing. Results : Systemic administration of aniracetam significantly increased overall social behavior time and frequency (Table 3). In addition, 8
With -OH-DPAT, both scores also increased in a dose-dependent manner. N-Anisoyl-GABA had no effect, while p-anisic acid tended to increase both overall social behavior time and frequency.

[0028]

[Table 3]

The data are expressed as mean ±
S. E. FIG. M. Represents * Is P <0.05; ** is P <0.01 relative to the corresponding vehicle control group.

Example 5 Forced Swim Test Animals : Male Wistar Rats 25-30 Months Old Test Method : In a training session on day 1, each rat was placed in water at 23 ± 1 ° C. (45 cm deep). Was placed in a cylinder (diameter 30 cm × 60 cm). Fifteen
After a minute, the rats were removed and dried. In the test session on the second day (24 hours after the training session), the rats were allowed to swim again for 5 minutes and the immobility time was measured. This condition was considered immobile when the rat floated in the water without struggling and made only the movements necessary to keep its head above the water. Compounds were administered immediately after a 15-minute swim on day 1 and 4 and 0.5 hours (1 hour for oral administration) before a 5-minute swim on day 2. Test results : As shown in Table 4, acute administration of aniracetam (three times in two days) significantly reduced immobility time, imipramine (tricyclic antidepressant), bromocriptine and lazabemide (monoamine-B). Oxidase inhibitors). All three metabolites of aniracetam were in themselves ineffective, but N-anisoyl-G
Co-administration of ABA and 2-pyrrolidinone significantly reduced immobility time (FIG. 3). The combination of p-anisic acid and 2-pyrrolidinone also showed a tendency to shorten.

[0031]

[Table 4]

The data are the mean ± immobility time on the second day ±
S. E. FIG. M. Represents * Indicates P <0.05; ** indicates P <0.01, ** for the corresponding vehicle control group.
* Indicates P <0.001.

N-Anisoyl-GABA is an anxiety disorder, such as GAD, OCD, SAD, PD and PTSD; depression, such as cerebrovascular and major depression; schizophrenia, such as social withdrawal; ;
It is also useful as a therapeutic agent for various neuropsychiatric symptoms such as autism, immature emotion.

Examples of pharmaceutically acceptable preparations are shown below, but the present invention is not limited thereto. Example 6 Preparation of Pharmaceutical Composition 4.1 N-Anisoyl-GABA or p-anisic acid
Preparation of Tablets Containing Tablets containing 100 mg of N-anisoyl-GABA or p-anisic acid were prepared using the following composition (per tablet) by the following method. Composition A: N-Anisoyl-GABA or p-anisic acid 100 mg Lactose 20 mg Kollidon CL (BASF) 15 mg Maize starch 30 mg Avicel PH101 (Asahi Kasei) 50 mg Composition B: polyvinylpyrrolidinone K-90 5 mg light anhydrous Silicic acid 18mg Magnesium stearate 2mg Total 240mg

The mixture of the above composition A was kneaded with an 8% aqueous solution of polyvinylpyrrolidinone K-90. After drying at 60 ° C., Composition B was mixed therewith. The mixture was compressed into round tablets having a weight of 240 mg and a diameter of 8 mm.

4.2 N-Anisoyl-GABA or p
Preparation of Capsules Containing Anisic Acid Capsules containing 100 mg of N-anisoyl-GABA or p-anisic acid were prepared by the following method using the following composition (per capsule). Composition A: N-Anisoyl-GABA or p-anisic acid 100 mg Lactose 20 mg Kollidon CL (BASF) 2 mg Maize starch 53 mg Composition B: polyvinylpyrrolidinone K-90 5 mg Avicel PH101 (Asahi Kasei) 18 mg stearic acid Magnesium 2mg Total 200mg

The mixture of the above composition A was kneaded with an 8% aqueous solution of polyvinylpyrrolidinone K-90. After drying at 60 ° C., Composition B was mixed therewith. The mixture was poured into No. 3 gelatin capsules to give capsules containing 200 mg.

[Brief description of the drawings]

1 shows the effect of systemic administration of aniracetam on DA and 5-HT release in the prefrontal cortex of SHRSP under ambulatory behavior.

FIG. 2. Local perfusion of anilacetam and its metabolites into the ventral tegmental area (A) or the prefrontal cortex (B) of aniracetam and its metabolites on DA and 5-HT release in the prefrontal cortex of the freely moving SHRSP. Show the effect.

FIG. 3 shows the effect of aniracetam metabolite alone or various combinations of two metabolites on immobility time in a forced swimming test using aged rats.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Mitsue Kurasawa 794-7 Iwase, Kamakura City, Kanagawa Prefecture (72) Inventor Yushiro Tanaka 262-3-3, Kamigocho, Sakae-ku, Yokohama-shi, Kanagawa Prefecture 509 F-term (reference) 4C206 AA01 AA02 DA19 FA45 GA08 MA04 MA51 MA55 MA86 NA14 ZA12 ZA18 ZC02

Claims (6)

[Claims] 1. A pharmaceutical composition for promoting dopamine and serotonin release in the brain, comprising N-anisoyl-γ-aminobutyric acid or p-anisic acid as an active ingredient and a therapeutically inert carrier. 2. General anxiety disorder, obsessive-compulsive disorder, social anxiety disorder, panic disorder and trauma, comprising N-anisoyl-γ-aminobutyric acid or p-anisic acid as an active ingredient and a therapeutically inert carrier. Pharmaceutical compositions for treating anxiety such as post-stress disorders; depressive disorders such as cerebrovascular and major depression; schizophrenia such as social withdrawal; and autism such as emotional immaturity. 3. The method according to claim 1, wherein the active ingredient is N-anisoyl-γ-aminobutyric acid or p-anisic acid in an amount of from 1 to 300 per day.
The pharmaceutical composition according to claim 1 or 2, which is administered at a dose of mg / kg. 4. N-Anisoyl- for the manufacture of a pharmaceutical composition for promoting dopamine and serotonin release in the brain.
Use of γ-aminobutyric acid or p-anisic acid. 5. Anxiety disorders such as generalized anxiety disorder, obsessive-compulsive disorder, social anxiety disorder, panic disorder and post-traumatic stress disorder; depression such as cerebrovascular depression and major depression; social withdrawal Use of N-anisoyl-γ-aminobutyric acid or p-anisic acid for the manufacture of a pharmaceutical composition for treating autism such as schizophrenia; and emotional immaturity. 6. The method according to claim 1, wherein the active ingredient, N-anisoyl-γ-aminobutyric acid or p-anisic acid, is contained in an adult in an amount of 1 to 30 per day.
6. Use according to claim 4 or claim 5 which is present in a unit dose of 0 mg / kg.