Use of cyclo-glycine-proline for the preparation of a medicament for the treatment of binge eating disorder

Abstract

The application discloses application of cyclo-glycine-proline in preparation of a drug for treating binge eating disorder. The cyclo-glycine-proline is applied in preparation of the drug for treating binge eating disorder. The cyclo-glycine-proline is applied in preparation of an active ingredient of the drug for treating binge eating disorder (specifically, binge eating disorder caused by emotional eating induced by social psychological stress). The cyclo-glycine-proline has the advantages of small molecular weight, strong lipophilicity, enzymatic stability, high oral bioavailability and the like, and can be effectively absorbed by the central nervous system. The application has great application value for treatment of binge eating disorder (especially binge eating disorder induced by emotional eating).

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug application for treating binge eating disorder, and relates to the application of cyclo-glycine-proline in the preparation of a drug for treating binge eating disorder. BACKGROUND

[0002] Obesity has become a major global public health problem. Obesity increases the risk of developing a variety of diseases, including type 2 diabetes, high blood pressure and high cholesterol, musculoskeletal problems, and various types of cancer. Binge eating disorder is often associated with obesity and concurrent physical and mental health complications. In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), binge eating disorder (BED) is defined as "recurrent episodes of eating significantly more food in a short period of time than most people would eat under similar circumstances, with episodes characterized by a lack of control". It is estimated that the global prevalence of binge eating disorder among adult women was 0.6% to 1.8% and among adult men was 0.3% to 0.7% between 2018 and 2020. Existing research shows that emotional dysregulation and emotional state affect eating behavior and play a crucial role in the development and persistence of obesity.

[0003] Negative emotions and stress can lead to overeating, which is known as emotional eating. Emotional eating is not an independent eating disorder, but an eating behavior influenced by behaviors related to eating, stress, emotions, and personal feelings. Emotional eating or comfort eating, as well as stress-induced eating, both lead individuals to eat when they experience negative emotions. Emotional eating is positively correlated with increased body weight gain over time. This can be attributed to the fact that emotional eaters are more likely to consume large amounts of sugar and high-fat foods, eat in stressful situations, and snack more frequently than non-emotional eaters. These eating behaviors serve as a coping mechanism to control and alleviate negative emotions such as low mood, anxiety, and stress. In addition, emotional eating is often seen as a major influencing factor in models of eating disorders and pathological eating attitudes (such as overeating and binge eating), and can lead to serious psychological distress and health problems.

[0004] Insulin-like growth factor 1 (IGF-1) is produced in many organs and has biological effects on most cells. It can stimulate amino acid transport, protein synthesis and body growth. In patients with eating disorders, IGF-1 is closely related to body mass index (BMI), body fat and body muscle mass. Cyclic glycine-proline (cGP) is a natural substance produced after the cyclization of the N-terminal tripeptide of IGF-1. cGP has the advantages of small molecular weight, strong lipophilicity, enzymatic stability, high oral bioavailability, and can be effectively absorbed by the central nervous system. However, whether cGP has the potential for improving the treatment of long-term psychosocial stress-induced binge eating has not been evaluated. SUMMARY

[0005] The purpose of the present application is to provide the use of cyclic glycine-proline in the preparation of a drug for treating binge eating.

[0006] The present application aims at the structurally stable cyclic dipeptide cyclic glycine-proline (cGP), and evaluates its biological activity in the drug treatment of binge eating from the perspective of improving emotional eating, which has great application value for the treatment of binge eating.

[0007] The present application provides the use of cyclic glycine-proline or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating binge eating.

[0008] The structural formula of the cyclic glycine-proline is shown in the following formula I:

[0009] .

[0010] In the present application, the cyclic glycine-proline has the English name Cyclic glycine-proline, the English abbreviation cGP, the molecular formula C7H 10 N2O2, and the molecular weight is 154.17.

[0011] In the above application, the binge eating is binge eating induced by emotional eating.

[0012] In the above application, the binge eating is binge eating caused by negative emotions induced by long-term psychosocial stress.

[0013] In the above application, the binge eating is binge eating caused by cognitive dysfunction induced by long-term psychosocial stress.

[0014] In the above application, the dosage form of the drug is a gastrointestinal administration dosage form or a non-gastrointestinal administration dosage form.

[0015] In the above-mentioned application, the gastrointestinal administration dosage form includes a powder, a tablet, a granule, a capsule, a solution, an emulsion or a suspension; and the parenteral administration dosage form includes an injection.

[0016] In the above-mentioned application, the treatment of the subject with binge eating is manifested by improving emotional eating in mice, reducing negative emotions induced by long-term psychosocial stress, and enhancing cognitive function of emotional eating mice.

[0017] In the above-mentioned application, the pharmaceutically acceptable salt of the cyclic glycine-proline is at least one of hydrochloride, nitrate, methanesulfonate, phosphate, citrate, fumarate, sulfate, succinate, tartrate, citrate, hydrobromide, hydroiodide, acetate, lactate, benzenesulfonate, cinnamate, salicylate, malonate, glutarate, malate.

[0018] The present application also provides a pharmaceutical composition for treating binge eating, which comprises the cyclic glycine-proline or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0019] In the above-mentioned pharmaceutical composition, the dosage form of the pharmaceutical composition includes a powder, a tablet, a granule, a capsule, a solution, an emulsion, a suspension or an injection.

[0020] The present application has the following advantages:

[0021] The cyclic glycine-proline (cGP) of the present application is used in the preparation of an active ingredient for treating binge eating (particularly binge eating induced by emotional eating). The cGP has the advantages of small molecular weight, strong lipophilicity, enzyme stability, high oral bioavailability, and effective absorption by the central nervous system. The present application has great application value in the treatment of binge eating (particularly binge eating induced by emotional eating). BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 is a schematic diagram showing the results of long-term psychosocial stress-induced feeding disorders and negative emotions in mice, Figure 1 A in the above-mentioned application represents an experimental flowchart showing long-term psychosocial stress-induced feeding disorders and negative emotions in mice, B represents daily food intake, C represents body weight change, D represents a novel environment-induced feeding inhibition experiment, E represents a high-elevated plus maze experiment, F represents a spontaneous activity test, G represents a social interaction behavior test, H represents a forced swimming experiment, I represents a tail suspension experiment, J represents a novel object recognition experiment-the time of the mouse in the novel object, and K represents a novel object recognition experiment-the recognition index of the mouse to the novel object.

[0023] Figure 2 is a schematic diagram of the results of cyclo-glycine-proline improving emotional feeding in mice, Figure 2 A indicates the experimental flow chart of cyclo-glycine-proline improving emotional feeding in mice, B indicates the daily food intake, and C indicates the body weight change.

[0024] Figure 3 is a schematic diagram of the results of cyclo-glycine-proline reducing long-term psychosocial stress-induced anxiety behavior, Figure 3 A indicates the experimental flow chart of cyclo-glycine-proline reducing long-term psychosocial stress-induced anxiety behavior, B indicates the novel environment food intake inhibition test, C indicates the elevated plus maze test, and D indicates the spontaneous activity test.

[0025] Figure 4 is a schematic diagram of the results of cyclo-glycine-proline reducing long-term psychosocial stress-induced depression behavior, Figure 4 A indicates the experimental flow chart of cyclo-glycine-proline reducing long-term psychosocial stress-induced depression behavior, B indicates the social interaction test, C indicates the forced swim test, and D indicates the tail suspension test.

[0026] Figure 5 is a schematic diagram of the results of cyclo-glycine-proline enhancing the cognitive function of emotional feeding mice, Figure 5 A indicates the experimental flow chart of cyclo-glycine-proline enhancing the cognitive function of emotional feeding mice, B indicates the novel object recognition test - the time the mouse stays in the new object, and C indicates the novel object recognition test - the recognition index of the mouse to the new object. DETAILED DESCRIPTION

[0027] The experimental methods used in the following examples are conventional methods unless otherwise specified.

[0028] The materials, reagents, etc. used in the following examples can be obtained from commercial channels unless otherwise specified.

[0029] In the following examples, cyclo-glycine-proline (cGP) was purchased from Bachem (G-1720), and the preparation method of cGP was 3 mg dissolved in 20 ml of physiological saline, the intragastric volume was 0.2 ml / 10g body weight, and the intragastric dose of mice was 3 mg / kg.

[0030] In the following examples, high-fat feed was purchased from Boaopai Biotechnology Co., Ltd., and the food ingredients included corn starch (115.5 g / kg), casein (200 g / kg), sucrose (100 g / kg), dextrin starch (132 g / kg), lard (312 g / kg), soybean oil (40 g / kg), cellulose (50 g / kg), minerals (35 g / kg), vitamins (10 g / kg), L-cysteine (3 g / kg), and choline (2.5 g / kg), wherein 60% of the calories came from fat.

[0031] In the following examples, the experimental animals were 3-week-old C57BL / 6J female mice (body weight 7-9 g) purchased from Beijing Huafukang Biosciences Co., Ltd., license number: SCXK (Jing) 2019-0008. The animals were raised in a SPF-grade animal room, and the feeding conditions were maintained at a temperature of (22±2°C), a humidity of (50±10%), and a 12h circadian rhythm cycle (8:00-20:00 as the light period). The animals could freely drink water and eat, and the behavior evaluation was performed during the dark period. All operations received by the animals complied with the requirements of experimental animal ethics and followed the regulations promulgated by the National and Beijing University of Medicine Animal Use and Protection Committee.

[0032] Establishment of a long-term psychosocial stress animal model: In the process of biological evolution, social interaction becomes an essential need for socialized animals, like eating, drinking, and sleeping. Therefore, lack of social interaction or even social isolation is a kind of psychosocial stress, which universally negatively affects mental health at all ages and even increases the risk of various mental disorders. In this experiment, we established a long-term psychosocial stress model by social isolation of mice, referring to previous studies. From the 21st day after birth, female C57BL / 6J mice were raised in single cages (Isolation) or in groups (Control) for 8 weeks, and both groups of mice were given high-fat food at a regular feeding amount. Before and during the experiment, the food intake and body weight of the animals in each group were recorded daily. After 8 weeks, the behavior of the mice was detected by social behavior experiment, spontaneous activity test, new environment inhibition of food intake experiment, elevated plus maze test, forced swimming experiment, tail suspension experiment, and new object recognition, and the effects of long-term psychosocial stress on food intake, body weight, negative emotions, and cognitive function of mice were analyzed.

[0033] Social behavior test: The social behavior experiment was divided into two stages, each stage lasted for 2.5 min, and the interval between the two stages was 30 s. The experiment was carried out in a 42 cm x 42 cm x 25 cm open field. In the first stage, the C57BL / 6J test mouse was randomly placed in the corner far from the interaction area, and a 3 cm x 6 cm x 25 cm plastic transparent box with small holes was placed in the interaction area. The box was not placed with a mouse, and the C57BL / 6J test mouse was allowed to freely move in the open field, and the time of the C57BL / 6 test mouse staying in the interaction area was recorded. In the second stage, a mouse was placed in the transparent box, and the C57BL / 6 test mouse was placed back in the corner of the open field. The interaction between the C57BL / 6J test mouse and the mouse was observed, and the time (seconds) of the C57BL / 6 test mouse in the interaction area was recorded.

[0034] Spontaneous activity test: The open field experiment was carried out in a 42 cm x 42 cm x 25 cm open field. The mouse was placed in the center of the open field, and the activity distance of the mouse in 5 min was recorded as the evaluation standard of the spontaneous activity level of the animal.

[0035] Novel environment inhibits feeding experiment: The mice were subjected to 24 h fasting before the test. The test was carried out in a 42 cm x 42 cm x 42 cm open-top opaque acrylic plate box. Four food particles of similar size were placed in the central area of the test box. The mouse was gently placed into the test box from the corner to start the test. The time from the start of the test to the mouse ingesting food was the feeding latency (Latency to feed), which was used as an index for evaluating anxiety-like behavior. During the test, the mouse was allowed to freely explore the test box for 10 min, and the longest latency was 600 s. After the test, the mouse was placed back into the original living cage. The excrement left in the test box was cleaned every two mice, and the test box was wiped with 75% alcohol to remove the residual odor.

[0036] Elevated plus maze test: The mouse elevated plus maze test device was composed of two open arms (30 cm x 5 cm), two closed arms (30 cm x 5 cm, 23 cm high) and a central area (5 cm x 5 cm). The open arms were 75 cm away from the ground. The mouse was gently placed in the central area at the beginning of the test, and the head of the mouse was directed towards the open arm. The mouse was allowed to freely explore the elevated plus maze for 6 min. The time (s) of the mouse staying in the open arm was recorded as an index for evaluating anxiety-like behavior. The excrement left in the test box was cleaned every two mice, and the test box was wiped with 75% alcohol to remove the residual odor.

[0037] Forced swimming test: The forced swimming test was performed in a 20 cm in diameter and 30 cm in height glass cylinder with 15 cm water depth and water temperature of 23 ± 1℃. The mice were allowed to swim without support from their limbs or tail and with their snout above water. The swimming time was 6 min, and the floating time (seconds) of the mice was recorded as an index of despair behavior after 2 min of adaptation.

[0038] Tail suspension test: In the tail suspension test device, the mice were fixed at the tail tip 1 cm away from the white adhesive tape on the suspension rod of the tail suspension test device, suspended for 6 min, and the immobile time (seconds) of the mice in the last 5 min was recorded.

[0039] Novel object recognition test: The novel object recognition test of mice was divided into two stages, each stage for 3 min, and the interval between the two stages was 15 min. The experiment was performed in a 40 cm × 27 cm × 18 cm open field. In the first stage, two identical objects A were placed in the center of the open field, and the test mice were placed from the corner to freely explore the two identical objects A. In the second stage, familiar object A and new object B were placed in the center of the open field, and object B and object A were different in shape, material and color. The test mice were allowed to freely explore in the open field, and the time of exploring object A and object B was recorded respectively. The cognitive ability of the mice was evaluated by the novel object recognition index, and the novel object recognition index = exploring time of object B / (exploring time of object A + exploring time of object B).

[0040] Data statistics:

[0041] Data analysis was performed using GraphPad Prism 8 software (GraphPad Software Inc.). The results were expressed as mean ± standard error (mean ± SEM). The results of two-way ANOVA Bonferronis multiple intergroup analysis were used. The difference between the two groups was analyzed by Two-tailed unpaired t-test. P < 0.05 was considered as a significant difference. p <0.05 as a significant difference standard.

[0042] Example 1, long-term psychosocial stress induced mice to develop eating disorders and negative emotions

[0043] The experiment used 18 3-week-old C57BL / 6J female mice, which were randomly divided into two groups: a normal group-housed (Control) group and a social isolation (Isolation) group, with 9 mice in each group. Before the start of the experiment, the daily food intake and body weight of the two groups of mice were measured, which was the baseline value (Baseline). Subsequently, the mice in the social isolation (Isolation) group were housed in single cages (that is, 1 mouse was placed in each standard cage), and 4-5 mice were placed in each standard cage in the normal group-housed (Control) group. The whole process lasted for 8 weeks. During this process, both groups of mice were given a regular amount of high-fat feed. After the end of the 8th week, the mice's eating habits and body weight (recorded as Week-8), as well as negative emotions of anxiety and depression and cognitive function, were tested. All experiments were completed within one week. During this process, each group of mice still maintained their original handling mode and eating habits. The experimental process is as follows: Figure 1 As shown in A, the specific results are as follows:

[0044] Mice that underwent eight weeks of social isolation showed an increase in their intake of high-fat food compared to their baseline values. p <0.001, e.g. Figure 1 However, the food intake of mice in the normal group (Control) did not differ significantly from the baseline value at Week 8. At Week 8, the food intake of the Isolation group was significantly increased compared with the Control group ( p <0.001, e.g. Figure 1 This indicates that the psychosocial stress caused by long-term social isolation increases the intake of high-fat food in mice. In addition, the data from animal weight monitoring showed that compared with the baseline value (Baseline), both the Isolation group and the Control group showed a trend of weight gain; however, at Week 8 (Week-8), the weight gain of the Isolation group mice was more significant compared with the Control group ( p <0.001, e.g. Figure 1 C), indicating that long-term psychosocial stress increases food intake and body weight in mice.

[0045] The results of the novel environment inhibition feeding experiment showed that after 8 weeks of social isolation, mice showed a longer latency to feed compared with the control group ( p <0.001, e.g. Figure 1 In the elevated plus maze test, the socially isolated mice (Isolation) spent less time in the open arms compared to the control group (Control). p <0.001, e.g. Figure 1There was no significant difference between the two groups of mice in the spontaneous activity test ( p >0.05, e.g. Figure 1 (As shown in F), suggesting that 8 weeks of social isolation will not affect the normal activity of mice, but will increase their anxiety behavior. The results of the social behavior test showed that mice isolated for 8 weeks showed obvious social avoidance behavior, that is, the interaction ratio in the interaction area decreased significantly ( p <0.01, e.g. Figure 1 In the forced swimming test, social isolation mice showed a significant increase in immobility time ( p <0.001, e.g. Figure 1 In the tail suspension test, social isolation mice also showed a significant increase in immobility time ( p <0.001, e.g. Figure 1 In the novel object recognition test to evaluate cognitive ability, social isolation mice showed a decrease in the time they spent on the novel object ( p <0.001, e.g. Figure 1 J in the middle), and those with a lower recognition index ( p <0.001, e.g. Figure 2 K in the middle), suggesting that the cognitive abilities of mice were impaired.

[0046] These results suggest that the psychological stress caused by long-term social isolation not only leads to eating disorders and weight gain in mice, but also increases negative emotions such as anxiety and depression, accompanied by decreased cognitive function. This further confirms that emotional regulation disorders and mood states do affect eating behavior, and that enhancing cognitive abilities to reduce emotional eating is expected to improve eating disorders and the binge eating behaviors that result.

[0047] Example 2: Cycloglycine-proline improves emotional eating in mice

[0048] The experimental process is as follows Figure 2 As shown in Figure A. After 8 weeks of social isolation and a high-fat diet, mice were randomly divided into two groups, each with 9 mice. Starting from the 9th week, the two groups were given saline and cycloglycine-proline (cGP, 3 mg / kg) by oral gavage once a day for 4 consecutive weeks. The animals' food intake and weight changes were measured at week 12. The experimental results showed that compared with the saline group, the mice treated with cGP for 4 weeks had a significant decrease in food intake ( p <0.001, e.g. Figure 2 Similarly, the body weight of mice treated with cGP also decreased significantly (p <0.001, e.g. Figure 3 These results indicate that cGP treatment can significantly improve emotional eating behavior and weight gain in mice induced by long-term psychosocial stress.

[0049] Example 3: Cycloglycine-proline reduces negative emotions induced by long-term psychosocial stress

[0050] This example first evaluates the effect of cycloglycine-proline (cGP) on anxiety-induced behavior in mice induced by long-term social and psychological stress. Figure 3 As shown in middle A. After 8 weeks of social isolation and high-fat diet intervention, mice were randomly divided into two groups, each with 9 mice. Starting from the 9th week, the two groups of animals were given saline and cycloglycine-proline (cGP, 3 mg / kg) by oral gavage once a day for 4 consecutive weeks. At the 12th week, the mice were tested for anxiety behavior by novel environment suppressed feeding, elevated plus maze, and spontaneous activity tests. The experimental results showed that compared with the saline group, the mice treated with cGP for 4 weeks had a significantly shorter latency to eat in the novel environment suppressed feeding test ( p <0.001, e.g. Figure 3 Mice in the cGP-treated group also spent more time in the open arms in the elevated plus maze test than mice in the saline group ( p <0.001, e.g. Figure 3 (as shown in middle C), indicating that the anxiety behavior of mice was alleviated; however, cGP intervention for 4 weeks did not affect the normal spontaneous activity ability of mice ( p >0.05, e.g. Figure 4 These results suggest that cGP treatment can significantly improve anxiety in mice induced by long-term psychosocial stress.

[0051] In addition, this example also evaluated the effect of cycloglycine-proline (cGP) on the depressive behavior of mice induced by long-term social and psychological stress. Figure 4 As shown in middle A. After 8 weeks of social isolation and high-fat diet intervention, mice were randomly divided into two groups, each with 9 mice. Starting from the 9th week, the two groups of animals were given saline and cycloglycine-proline (cGP, 3 mg / kg) by oral gavage once a day for 4 consecutive weeks. At the 12th week, social behavior, forced swim test, and tail suspension test were performed to detect depressive behavior in the mice. The results of the social behavior test showed that compared with the saline group, the mice treated with cGP for 4 weeks had a significantly increased interaction ratio ( p <0.0001, e.g.Figure 4 (B in the middle), indicating that cGP improved the social avoidance behavior of mice with long-term social and psychological stress. The results of the forced swimming test showed that compared with the saline group, the immobility time of mice treated with cGP for 4 weeks was significantly reduced ( p <0.0001, e.g. Figure 4 The tail suspension test also showed that the immobility time of mice treated with cGP for 4 weeks was significantly reduced compared with the saline group ( p <0.001, e.g. Figure 5 These results suggest that cycloglycine-proline (cGP) can reduce negative emotions induced by long-term psychosocial stress and has potential therapeutic value for binge eating disorder caused by emotional eating.

[0052] Example 4: Cyclic Glycine-Proline Enhances Cognitive Function in Emotionally Eating Mice

[0053] The experimental process is as follows Figure 5 As shown in Figure A. After 8 weeks of social isolation and a high-fat diet, mice were randomly divided into two groups of 9 each. Starting in the 9th week, the two groups were given saline and cycloglycine-proline (cGP, 3 mg / kg) by oral gavage once daily for 4 consecutive weeks. At the 12th week, a novel object recognition test was performed to assess the mice's cognitive function. The experimental test results showed that compared with the saline group, mice treated with cGP for 4 weeks had a stronger ability to explore novel objects, that is, they stayed in the novel object for a longer time ( p <0.0001, e.g. Figure 5 B), and also showed a higher recognition index ( p <0.01, e.g. ​ This result suggests that cycloglycine-proline (cGP) can improve the cognitive ability of mice subjected to long-term psychosocial stress.

Claims

1. Use of cycloglycine-proline or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating bulimia; The structural formula of the cycloglycine-proline is shown in Formula I below: 。 2. The use according to claim 1, characterized in that The binge eating disorder is binge eating disorder induced by emotional eating.

3. The use according to claim 1, characterized in that The bulimia nervosa is caused by negative emotions induced by long-term social and psychological stress.

4. The use according to claim 1, characterized in that The bulimia nervosa is caused by a decline in cognitive function induced by long-term psychosocial stress.

5. The use according to claim 1 or 2, characterized in that: The dosage form of the drug is a gastrointestinal dosage form or a parenteral dosage form.

6. The use according to claim 5, characterized in that The dosage form for administration via the gastrointestinal tract is selected from powders, tablets, granules, capsules, solutions, emulsions or suspensions; The parenteral dosage form is selected from injection.

7. The use according to claim 1 or 2, characterized in that The pharmaceutically acceptable salt of the cycloglycine-proline is selected from at least one of hydrochloride, nitrate, methanesulfonate, phosphate, citrate, fumarate, sulfate, succinate, tartrate, citrate, hydrobromide, hydroiodide, acetate, lactate, tosylate, cinnamate, salicylate, malonate, glutarate, and malate.

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