Application of benzenesulfonamide compound in preparation of antidepressant drug

Abstract

The invention discloses an application of a benzenesulfonamide compound in preparation of an antidepressant drug. The invention discloses that the benzenesulfonamide compound has anti-depression activity for the first time, not only can obviously improve behavior performance in various depression models, but also is good in safety, does not influence basic movement functions of animals, and provides a new choice for research and development of anti-depression drugs.

Description

Technical Field

[0001] This application specifically relates to the use of a benzenesulfonamide compound in the preparation of antidepressant drugs, and belongs to the field of biomedical technology. Background Technology

[0002] Depression is a mood disorder characterized by persistent low mood and anhedonia. According to the World Health Organization (WHO), depression is the leading cause of disability globally, affecting approximately 3.8% of the population, and its burden is increasing. The disease is characterized by its prolonged course and high relapse rate, posing significant challenges to clinical treatment. On the one hand, existing antidepressants have significant limitations, with approximately 30% of patients with severe depression not receiving adequate clinical response. On the other hand, their efficacy requires 3-6 weeks to develop, exhibiting a significant clinical delay, and generally suffers from delayed onset, insufficient efficacy, significant side effects, and tolerance with long-term use, failing to meet the urgent clinical need for highly effective, rapid, and stable antidepressant therapies. Therefore, developing antidepressants with novel mechanisms of action, rapid onset of action, and good safety profiles is of significant clinical and social value in improving the current state of depression treatment. Summary of the Invention

[0003] In order to overcome the shortcomings of the prior art and solve at least one of the technical problems mentioned in the background art, this application provides the following technical solution.

[0004] One aspect of this application provides the use of a benzenesulfonamide compound in the preparation of an antidepressant, said benzenesulfonamide compound having the structure shown below: .

[0005] In this application, the benzenesulfonamide compound may also be named SZ0232.

[0006] Furthermore, when the drug is applied to a mouse model, it can at least improve the mouse's behavioral despair.

[0007] Furthermore, when the drug is applied to a mouse model, it can at least shorten the immobility time of mice in the Forced Swim Test (FST) and / or reduce the immobility time of mice in the Tail Suspension Test (TST).

[0008] Furthermore, when the drug is applied to mouse models, it can at least induce social avoidance in depressed mouse models.

[0009] Furthermore, when the drug is applied to mouse models, it can at least increase the time mice spend exploring socially in the Social Interaction Test (SIT).

[0010] Furthermore, when the drug is applied to a mouse model, it can at least improve anhedonia in a depressed mouse model.

[0011] Furthermore, when the drug is applied to a mouse model, it can at least increase the sucrose preference rate in the sucrose preference test (SPT).

[0012] Furthermore, when the drug is applied to a mouse model, it does not affect the mouse's basic motor function; wherein the behavioral indicators of the motor function include the total distance of movement in an open field test.

[0013] Another aspect of this application provides a pharmaceutical composition for treating depression, comprising a benzenesulfonamide compound or a pharmaceutically acceptable derivative thereof, said benzenesulfonamide compound having the structure shown below: .

[0014] The pharmaceutically acceptable derivative is selected from at least one of pharmaceutically acceptable salts, polymorphs, eutectics, radiolabeled forms, and combinations thereof.

[0015] Furthermore, the pharmaceutical composition can significantly improve the behavior of test animals, such as despair in a depressed mouse model.

[0016] Furthermore, the pharmaceutical composition can at least shorten the immobility time of test animals in the forced swimming test and reduce the immobility time of test animals in the tail suspension test.

[0017] Furthermore, the pharmaceutical composition can significantly improve social avoidance in test animals, such as depressed mouse models.

[0018] Furthermore, the pharmaceutical composition is at least able to increase the social exploration time of test animals in social interaction tests.

[0019] Furthermore, the pharmaceutical composition can significantly improve anhedonia in test animals, such as depressed mouse models.

[0020] Furthermore, the pharmaceutical composition is at least able to increase the sugar water preference rate of the test animals in the sugar water preference experiment.

[0021] Furthermore, the pharmaceutical composition does not affect the basic motor function of the test animals. The behavioral indicators of said motor function include the total distance traveled in an open field test.

[0022] In this application, the test animals include mammals, such as mice.

[0023] In one embodiment, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier and / or excipient.

[0024] Furthermore, the carrier and / or excipient can be any known pharmaceutically acceptable carrier and excipient suitable for such use. The term "pharmaceutical carrier" as used herein has the meaning well known to those skilled in the art, and can include any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delay agents, salts, preservatives, pharmaceuticals, pharmaceutical stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, similar substances, and combinations thereof.

[0025] In some cases, the dosage form of the pharmaceutical composition includes any one of injection, oral liquid, capsule, tablet, and granule.

[0026] Compared with the prior art, this application discloses for the first time that the benzenesulfonamide compound has antidepressant activity. This compound can significantly improve behavioral performance in various depression models, and has good safety and does not affect basic motor function, providing a new option for the development of antidepressant drugs. Attached Figure Description

[0027] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0028] Figure 1 The figure shows the experimental results of the effect of SZ0232 on improving depressive-like behavior in a forced swimming experiment in one embodiment of this application; Figure 2 This is a diagram showing the experimental results of the effect of SZ0232 on improving depressive-like behavior in a tail suspension test in one embodiment of this application; Figure 3 This is a graph showing the experimental results of the effect of SZ0232 on improving depressive-like behavior in a social interaction experiment in one embodiment of this application; Figure 4 The figure shows the experimental results of the effect of SZ0232 on improving depressive-like behavior in a sucrose preference experiment in one embodiment of this application. Figure 5This is a diagram showing the experimental results of SZ0232 in an open field experiment in one embodiment of this application, demonstrating that it does not affect the general motor function of animals. Detailed Implementation

[0029] The technical solutions of this application will be clearly and completely described below with reference to embodiments. It should be understood that the described embodiments are only a part of the implementation methods of this application, and not all of them. Based on the content of this application, all other implementation methods obtained by those skilled in the art without creative effort are within the scope of protection of this application. The specific materials, reagents, instruments, and their sources used in the embodiments of this application are merely illustrative and do not constitute a limitation on this application. Any materials that are the same as or similar in type, model, quality, properties, or function to the reagents and instruments described can be used to implement this application. Unless otherwise specified, the experimental methods involved in the following embodiments are all conventional methods in the art, and the materials and reagents used can be obtained commercially.

[0030] 1. Laboratory animals: C57BL / 6J mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd., and bred at Xuzhou Medical University. The mice were housed in a standard animal room at a temperature of 23±2℃ and humidity of 40±10%, following a 12h / 12h (8:00 lighting) diurnal rhythm, with free access to food. This experiment was approved by the Animal Ethics Committee of Xuzhou Medical University and was conducted strictly in accordance with the laboratory animal care and usage guidelines.

[0031] 2. Reagents: SZ0232 was purchased from MCE. The sucrose used in the sugar preference experiment was purchased from Sinopharm Chemical Reagent Co., Ltd.

[0032] 3. Establishment of a mouse model of depression: CD1 mice were housed individually for 7 days to develop territorial awareness, while C57BL / 6 or transgenic mice (4-5 mice / cage) were housed for 7 days to acclimatize. ① Screening for aggressive retired CD1 breeding mice: Experimental mice were placed in CD1 mouse cages for 3 minutes. If a CD1 mouse initiated attacks more than twice with an attack latency of <1 minute, it was considered aggressive; mice exhibiting aggression for at least 2 out of 3 days could be used as aggressive mice in the model. ② Experimental group: Experimental group mice were placed in CD1 mouse cages and subjected to attacks for 5-10 minutes; then, the experimental group mice were isolated from CD1 mice for 24 hours using a perforated transparent acrylic plate, allowing the experimental group mice to receive visual, auditory, and olfactory contact from CD1 mice; for ten consecutive days, the experimental group mice were subjected to attacks from different CD1 mice each day to prevent acclimatization; after ten days, the experimental mice were removed and housed individually. ③ Control group: Mice of the same age as the experimental group were exposed to non-aggressive C57BL / 6 mice for 5-10 minutes each day; then isolated for 24 hours using the same acrylic plate; for ten consecutive days, new and different C57BL / 6 mice were introduced each day; after ten days, the experimental mice in the control group were removed and housed in individual cages.

[0033] 4. Experimental Design: SZ0232 was administered bilaterally to the ventral hippocampus via cannula at a concentration of 10 μM (using physiological saline as a solvent) and a volume of 0.8 μL per side for 3 consecutive days. The control group received an equal volume of physiological saline.

[0034] 5. Depressive-like behavior test: 5.1 Forced Swimming Experiment Mice were placed individually in a transparent cylindrical container 25 cm high and 15 cm in diameter, filled with 15 cm of water at a temperature of 25 ± 1 °C. The experiment lasted for 6 minutes, and the time the mice remained completely still (maintaining only necessary floating movements) for the last 5 minutes was recorded. The shorter the stillness time, the milder the despair-like behavior.

[0035] 5.2 Tail Suspension Experiment Using a specialized tail suspension device, the mouse's tail was taped to a horizontal bar 1-2 cm from the tip, suspending the mouse upside down with its head approximately 15 cm above the table. The experiment lasted 6 minutes, and the time the mouse remained completely still (without struggling, swaying, or other active behaviors) for the last 4 minutes was recorded. The shorter the stillness time, the lower the level of behavioral despair.

[0036] 5.3 Social Interaction Test The experimental setup consisted of an open box measuring 40×40×40cm, with a metal mesh cage (10×10×20cm) placed on one side inside. The test was conducted in two phases: Phase 1 (no social interaction), with an empty cage inside the box; Phase 2 (with a social interaction), with a strange mouse of the same strain placed inside the cage. Each phase lasted 10 minutes, and the exploration time of the experimental mouse within the social area (8cm around the cage) was recorded. Increased social exploration time reflected improved social avoidance behavior.

[0037] 5.4 Sugar Water Preference Experiment Mice were acclimatized for 48 hours before the experiment: on the first day, they were given two bottles of 1% sucrose solution; on the second day, one bottle was replaced with pure water. For the formal test, mice were fasted for 12 hours, then simultaneously given one bottle of 1% sucrose solution and one bottle of pure water; the weight of each bottle was measured beforehand. The weight of the bottles was measured again 24 hours later, and the sucrose preference rate was calculated. Sugar water preference rate = (Sugar water consumption / (Sugar water consumption + Pure water consumption)) × 100% The higher the preference rate, the milder the pleasure loss.

[0038] 6. Motor function test Open field test: A 50cm×50cm×40cm square open box was used, with the bottom divided into 16 equally sized squares. Mice were gently placed in the central square, and the total distance (in meters) of spontaneous movement and the time spent in the central area were recorded over 5 minutes. This test was used to assess the animals' general motor abilities and anxiety-like behaviors, ensuring that improvements in depressive-like behaviors were not caused by changes in motor function.

[0039] 7. Data Analysis All data are expressed as mean ± standard deviation (Mean ± SD). One-way ANOVA was first used for comparisons among multiple groups. If the ANOVA results showed significant differences, Bonferroni's multiple comparisons test was used for pairwise comparisons between groups. A p-value < 0.05 was considered statistically significant.

[0040] II. Experimental Results 1. SZ0232 significantly improves various depressive-like behaviors. After confirming that SZ0232 does not affect basic motor function, we systematically evaluated its behavioral effects in several classic depression models.

[0041] 1.1 SZ0232 Shortening the immobility time in the forced swimming experiment like Figure 1As shown, in the forced swimming experiment, compared with the saline control group, the mice in the SZ0232 administration group had a significantly shorter cumulative immobility time within 4 minutes after the test. This result indicates that SZ0232 can effectively alleviate the "behavioral despair" state in mice.

[0042] 1.2 SZ0232 Reduces the stationary time in the tail suspension experiment like Figure 2 As shown, in the tail suspension test, mice in the SZ0232-treated group showed a consistent improvement trend, with their cumulative immobility time being significantly less than that in the saline control group. This further confirms the efficacy of SZ0232 in alleviating the behavioral despair phenotype.

[0043] 1.3 SZ0232 adds social interaction testing and social exploration time. To evaluate the effect of SZ0232 on improving social avoidance behavior, we conducted a social interaction test. For example... Figure 3 As shown, during the social phase involving unfamiliar peers, mice in the SZ0232-treated group tended to spend more time exploring the social area (within an 8cm radius of the target cage) than the control group. This result suggests that SZ0232 can effectively improve the reduced social interest behavior associated with a depression model.

[0044] 1.4 SZ0232 Improves Sugar Water Preference Experiment Sugar Water Preference Rate To investigate the effect of SZ0232 on core symptoms of anhedonia, we conducted a sucrose preference experiment. (See also...) Figure 4 Statistical analysis showed that the saccharin preference rate in the SZ0232-treated group was significantly higher than that in the saline control group. This indicates that SZ0232 can reverse the decrease in reward sensitivity caused by depression and improve anhedonia symptoms.

[0045] 2. SZ0232 administration had no significant effect on the basic motor function of mice. To clarify that the antidepressant-like behavioral improvement effect of SZ0232 did not stem from its alteration of the animals' basic motor abilities, we first assessed its impact on spontaneous activity in each group of mice using an open field (OFT) test. The results are as follows: Figure 5 As shown, compared with the saline control group, there was no statistically significant difference in the total movement distance of mice in the SZ0232 administration group during the 5-minute test period. This result indicates that systemic administration of SZ0232, while exerting its subsequent behavioral effects, does not affect the mice's autonomous exploration activities or basic motor abilities, thus excluding the potential interference of hypermotor hyperactivity or inhibition on depressive-like behavioral indicators.

[0046] In summary, SZ0232, without affecting the animals' basic motor functions, can comprehensively and significantly improve the depression-like phenotypes evaluated by multiple behavioral paradigms (FST, TST, SIT, SPT), including behavioral hopelessness, social avoidance, and anhedonia, demonstrating its clear antidepressant potential.

[0047] The foregoing has shown and described the basic principles, main features, and advantages of this application. Those skilled in the art should understand that this application is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of this application. Various changes and modifications can be made to this application without departing from the spirit and scope thereof, and all such changes and modifications fall within the scope of this application as claimed. The scope of protection of this application is defined by the appended claims and their equivalents.

Claims

1. Use of a benzenesulfonamide compound in the preparation of an antidepressant, said benzenesulfonamide compound having the structure shown in the following formula: 。 2. The use according to claim 1, characterized in that: When the drug is applied to a mouse model, it can at least improve the mouse's behavioral despair.

3. The use according to claim 1, characterized in that: When the drug is applied to a mouse model, it can at least shorten the immobility time of mice in the forced swimming test and / or reduce the immobility time of mice in the tail suspension test.

4. The use according to claim 1, characterized in that: When the drug is applied to mouse models, it can at least induce social avoidance in depressed mouse models.

5. The use according to claim 1, characterized in that: When the drug is applied to mouse models, it can at least increase the time mice spend exploring socially in social interaction tests.

6. The use according to claim 1, characterized in that: When the drug is applied to mouse models, it can at least improve anhedonia in depressed mouse models.

7. The use according to claim 1, characterized in that: When the drug is applied to a mouse model, it can at least increase the sucrose preference rate in the sucrose preference experiment.

8. The use according to claim 1, characterized in that: When the drug is applied to a mouse model, it does not affect the mouse's basic motor function; wherein the behavioral indicators of the motor function include the total distance of movement in the open field test.

9. A pharmaceutical composition for treating depression, characterized in that, The compound comprises a benzenesulfonamide compound or a pharmaceutically acceptable derivative thereof, said benzenesulfonamide compound having the structure shown below: 。 10. The pharmaceutical composition according to claim 9, characterized in that, It also contains pharmaceutically acceptable carriers and / or excipients.

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