Application of selective 5-HT2AR bias agonist in preparation of medicine for treating mental disorder diseases

Abstract

The invention discloses an application of a selective 5-HT2AR biased agonist in preparation of a medicine for treating mental disorder diseases. The selective 5-HT2AR biased agonist is an agonist which selectively targets 5-HT2AR and is biased to Gq signal channel activity. The selective 5-HT2AR bias agonist provided by the invention is an agonist which selectively targets 5-HT2AR and has Gq signal path bias, has a remarkable effect in treating mental disorder diseases, and does not have side effects such as illusion.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technologies, and particularly to the use of a selective 5-HT 2A R-biased agonist in the preparation of a medicament for treating mental disorders. Background Art

[0002] Mental disorders are a class of diseases that seriously affect the physical and mental health and quality of life of humans, including various types such as depression, anxiety disorder, schizophrenia, etc. The occurrence and development of mental disorders seriously affect the quality of life and social functions of patients, and can cause huge losses to the global economic productivity. Currently, commonly used medicaments for treating mental disorders in clinical practice, such as the antidepressant Fluoxetine, etc., have many problems such as limited efficacy, large side effects, slow onset of action, etc.

[0003] Serotonin 2A receptor (5-HT2 A R) plays an important role in regulating emotions, cognition, etc., and is the main action target of many antipsychotic drugs, anti-anxiety drugs, etc. However, currently, medicaments for treating mental disorders using 5-HT 2A R have certain limitations: for example, psychoactive substances (such as DOI, LSD, etc.) as agonists of 5-HT 2A R have received extensive attention globally for their significant effects and fast onset of action in treating mood disorders, but they can cause side effects such as hallucinations and have safety risks such as abuse or misuse. Summary of the Invention

[0004] The present invention provides the use of a selective 5-HT 2A R-biased agonist in the preparation of a medicament for treating mental disorders in view of the problems existing in the prior art.

[0005] The use of a selective 5-HT 2A R-biased agonist in the preparation of a medicament for treating mental disorders, wherein the selective 5-HT 2A R-biased agonist is an agonist that selectively targets the activity of the 5-HT 2A R-biased G q signaling pathway.

[0006] Further, the selective 5-HT 2A R-biased agonist is:

[0007]

[0008] Further, the mental disorders include depression, schizophrenia, obsessive-compulsive disorder, and anxiety disorder.

[0009] A composition for preparing a drug for treating mental disorders, the composition comprising a selective 5-HT 2A R-biased agonist as described in any one of claims 1 to 3 and a pharmaceutically acceptable excipient.

[0010] Further, the excipient includes an excipient and an additive.

[0011] Further, the mental disorders include depression, schizophrenia, obsessive-compulsive disorder, and anxiety disorder.

[0012] Further, the selective 5-HT 2A R-biased agonist is:

[0013]

[0014] The beneficial effects of the present invention are:

[0015] The selective 5-HT 2A R-biased agonist of the present invention has a selective targeting of 5-HT 2A R and has a G q signal pathway-biased agonist, which has a significant effect in treating mental disorders and does not have side effects such as hallucinations. Description of the Drawings

[0016] Figure 1 It is a schematic diagram of the signal pathway transduction experiment of the compound DOI-NBOMe of the present invention.

[0017] Figure 2 It is the selective activation of 5-HT 2A R by the compound DOI-NBOMe of the present invention. a is the result of the G 1A pathway of 5-HT i R, and b to d are the results of the G 2A pathways of 5-HT 2B R, 5-HT 2C R, and 5-HT q R.

[0018] Figure 3 It is the statistical result of the G 2A signal pathway-biased activation of 5-HT q R by the compound DOI-NBOMe of the present invention.

[0019] Figure 4 It is the result of the head twitch experiment of mice in the embodiment of the present invention.

[0020] Figure 5 It is the result of the forced swimming experiment of mice in the embodiment of the present invention. a is the result 30 minutes after administration, and b is the result one week after administration.

[0021] Figure 6 The results of the marble burying test in mice in the embodiments of the present invention are shown. a is the result after 30 minutes of drug administration, and b is the result after 24 hours of drug administration. Detailed implementation manners

[0022] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0023] A selective 5-HT 2A R-biased agonist in the preparation of a medicament for treating mental disorders, the selective 5-HT 2A R-biased agonist is an agonist that selectively targets the activity of the 5-HT 2A R-biased G q signaling pathway. Its mechanism of action is as Figure 1 shown.

[0024] The selective 5-HT 2A R-biased agonist is:

[0025]

[0026] Mental disorders include depression, schizophrenia, obsessive-compulsive disorder, and anxiety disorder.

[0027] A composition for preparing a medicament for treating mental disorders, the composition comprising a selective 5-HT 2A R-biased agonist and a pharmaceutically acceptable excipient.

[0028] Currently, drugs targeting 5-HT 2A R for treating mental disorders have certain limitations: for example, psychoactive substances (such as DOI, LSD, etc.) as agonists of 5-HT 2A R have received extensive attention globally for their significant effects and rapid onset of action in treating mood disorders, but they can cause side effects such as hallucinations and have safety risks such as abuse or misuse. NBOMes is a new type of psychoactive substance. Compared with traditional psychoactive substances, they show higher affinity and stronger pharmacological activity for 5-HT 2A R, but also show more severe side reactions such as hallucinations. The compound used in the present invention is DOI-NBOMe (1-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]propan-2-amine), which does not cause hallucination behavior compared with existing drugs such as DOI and NBOMes.

[0029] In order to evaluate 5-HT 2AFor R-mediated G protein signal transduction and β-arrestin2 recruitment, we conducted BRET-based G protein dissociation experiments and cellular signaling experiments for β-arrestin2 recruitment. The HEK293 cell line with epithelial morphology isolated from human embryonic kidneys was cultured in high-glucose DMEM medium containing 10% fetal bovine serum in a cell culture incubator at 37°C and 5% CO2. In the G protein dissociation assay, 5-HT 1A R-WT or 5-HT 2A R-WT or 5-HT 2B R-WT or 5-HT 2C R-WT, G αq -NLuc, G αi -NLuc, G β3 and G γ9 -mVenus were co-transfected into HEK293 cells at an equal ratio (1:1:1:1:1). For the β-arrestin2 recruitment assay, 5-HT 2A R-mVenus and NLuc-β-arrestin2 were co-transfected into HEK293 cells at a ratio of 5:1. Transfection was performed using PEI. Twenty-four hours after transfection, the cells were digested and plated onto a 96-well white plate. The next day, the culture medium was aspirated, and 90 μL of detection buffer containing 5 μM Coelenterazine h (CTZ-h) was added and incubated at room temperature for 5 minutes. Using Multimode Microplate Reader (TECAN), the baseline signal was measured, and then 10 μL of agonist was added. After incubation for 5 minutes, the signal was read and data analysis was performed.

[0030] As can be seen from Figure 2 a, compared with the control group DOI, the use of DOI-NBOMe did not activate 5-HT 1A R, and the therapeutic effect of DOI-NBOMe did not depend on the G 1A signal pathway of 5-HT i R. As can be seen from Figure 2 b and c, compared with the control group DOI, DOI-MBOMe was selective among the three subtypes of the 5-HT2R family and could selectively activate the G 2A signal pathway of 5-HT q R. As can be seen from Figure 2 and Figure 3 , compared with the control group DOI, DOI-NBOMe was a G q signal pathway-biased agonist of 5-HT 2A R. In summary, it can be seen that DOI-NBOMe can selectively act on 5-HT 2AR and has G q Signal pathway bias.

[0031] To illustrate whether the agonist of the present invention can cause hallucinatory behavior

[0032] The head twitch response (HTR) in mice was used to detect whether DOI-NBOMe could cause hallucinatory responses. First, adult male C57BL / 6J mice (8-10 weeks old) were selected and housed under a 12-hour light-dark reverse cycle with controlled room temperature and humidity. After the mice arrived, they were left undisturbed for one week before the experiment and housed in a specific pathogen-free (SPF) animal experimental center, with free access to food and water. The mice were randomly divided into 5 groups: normal control group (Vehicle), DOI-NBOMe (2 mg / kg) intervention group, DOI-NBOMe (2 mg / kg) + 5-HT 2A R antagonist MDL intervention group, DOI-NBOMe (0.5 mg / kg) intervention group, and positive drug DOI intervention group. After intraperitoneal injection of the test compound according to the grouping, the mice were placed in an observation box and video-recorded. Subsequently, two independent observers quantified the twitch behavior based on the video recording. If the difference between the observers was 3 or less, the average value was calculated. If the difference exceeded 3, a more experienced assessor was asked to re-evaluate, and the results were as Figure 4 shown.

[0033] A corticosterone (CORT)-induced depressive-like mouse model was used. First, adult male C57BL / 6J mice (8-10 weeks old) were selected and housed under a 12-hour light-dark reverse cycle with controlled room temperature and humidity. After the mice arrived, they were left undisturbed for one week before the experiment and housed in a specific pathogen-free (SPF) animal experimental center, with free access to food and water. One week later, corticosterone at a concentration of 100 μg / mL was dissolved in the drinking water of male C57BL / 6J mice, except for the normal control group. The corticosterone-containing water was provided continuously for 21 days, and the drinking water was prepared and changed every other day. After 21 days of exposure to corticosterone, the therapeutic effect of DOI-NBOMe on depressive symptoms was evaluated by the forced swimming test. The mice were randomly divided into 6 groups: normal control group (Vehicle), model control group (Saline), DOI-NBOMe (2 mg / kg) intervention group, DOI-NBOMe (2 mg / kg) + 5-HT 2AThe MDL intervention group of R antagonist, the DOI-NBOMe (0.5 mg / kg) intervention group, and the positive drug Fluoxetine intervention group. According to the grouping, the compounds to be detected were intraperitoneally injected. After that, each mouse was separately placed in a glass cylindrical bucket filled with water, with a water depth of 25 cm and the temperature maintained at 24 ± 1 °C. Each mouse received 6 minutes of forced swimming training and was recorded with a camera. The immobility time was evaluated in the last 5 minutes of the test and analyzed using behavioral analysis software (Ethovision XT 13, Noldus). After the experiment, the mice were caged according to the grouping and continued to be raised in the animal experiment center, freely obtaining food and normal water. After one week of cultivation, the second forced swimming experiment was directly carried out according to the grouping, and the method and analysis were the same as above. The results are as Figure 5 shown.

[0034] The marble burying test (MBT) of mice was used to evaluate the effect of DOI-NBOMe on anxiety / obsessive-compulsive symptoms in mental disorders. The mice were randomly divided into 6 groups: normal control group (Vehicle), normal control + 5-HT 2A MDL intervention group of R antagonist, DOI intervention group, DOI + 5-HT 2A MDL intervention group of R antagonist, DOI-NBOMe intervention group, and DOI-NBOMe + 5-HT 2A MDL intervention group of R antagonist. At the beginning of the experiment, the mice were placed in a corner of a new observation box (46 × 22 × 20 cm), and the observation box was lined with 6 cm thick corncob bedding (diameter: 3 - 4 mm). A total of 21 marbles (diameter: 1.4 cm) were evenly arranged on the surface of the bedding in a 7 × 3 grid. The mice were allowed to freely explore the field for 30 minutes. After the test, the number of buried marbles was recorded by three experimenters who were kept secret about the experimental conditions. If the marble was partially covered by the bedding, it was considered buried. The scores of all observers were averaged for analysis. The results are as Figure 6 shown.

[0035] Figure 4 As can be seen in, DOI-NBOMe does not cause hallucinatory responses in mice. As can be seen in a of Figure 5 , DOI-NBOMe can regulate the immobility behavior of corticosterone-induced depressive-like mice, and the selective inhibitor of 5-HT 2A R (MDL100907) can block this effect. The number of mice used in the experiment corresponds to the points in the figure. *p < 0.033, **p < 0.002; ns, not significant; As can be seen in b of Figure 5 , the long-term effect of DOI-NBOMe on the forced swimming experiment. As can be seen in Figure 6As can be seen, the number of mice used in the experiment corresponds to the points in the figure. *p < 0.033, ns, not significant; d - e, total number of marbles buried by mice during MBT 30 minutes (a) and 24 hours (b) after injection of DOI and DOI - NBOMe (n = 12 mice per group). *p < 0.033, **p < 0.002, ***p < 0.001; ns, not significant.

[0036] As can be seen from Figure 4 that there was no significant difference in the number of head twitches between the group intervened with DOI - NBOMe and the normal group. However, the mice in the positive control DOI group had obvious head twitch responses and were statistically significant compared with the control group (p < 0.001).

[0037] To evaluate whether DOI - MBOMe has antidepressant effects, we conducted a forced swimming test on mice. As can be seen from Figure 5 Figure a, compared with the normal control group, the immobility time of mice increased significantly after CORT modeling in the FST, indicating that the mice had a depressive - like phenotype. Compared with the model group, the immobility time of the DOI - NBOMe (2 mg / kg) intervention group decreased significantly (p < 0.033), indicating that DOI - NBOMe (2 mg / kg) had a therapeutic effect on depressive mice models. Compared with the model group, there was no statistical significance in the DOI - NBOMe + 5 - HT 2A R antagonist MDL intervention group, indicating that DOI - NBOMe exerted its antidepressant effect through 5 - HT 2A R. Compared with the model group, the immobility time of the DOI - NBOMe (0.5 mg / kg) intervention group decreased significantly (p < 0.002), indicating that DOI - NBOMe (0.5 mg / kg) had a therapeutic effect on depressive mice models. Compared with the model group, there was no statistical significance in the positive control Fluoxetine intervention group, indicating that DOI - NBOMe had a faster onset of action in treating depression than Fluoxetin.

[0038] As can be seen from Figure 5 Figure b, one week later, compared with the normal control group, the immobility time of the mouse model group was statistically significant (p < 0.033), indicating that the mice still had a depressive - like phenotype. Compared with the model group, the immobility time of the DOI - NBOMe (2 mg / kg) intervention group decreased significantly (p < 0.033), indicating that the depressive - like mice treated with DOI - NBOMe (2 mg / kg) still showed a therapeutic effect one week later. Compared with the model group, DOI - NBOMe + 5 - HT 2AThere was no statistical significance in the MDL intervention group of R antagonists, indicating that DOI-NBOMe exerts a therapeutic effect on depression through 5-HT 2A R; compared with the model group, there was no statistical significance in the immobility time of mice in the DOI-NBOMe (0.5 mg / kg) intervention group; compared with the model group, there was no statistical significance in the immobility time of mice in the positive control Fluoxetine intervention group. These results confirmed that the selective 5-HT 2A R G q signaling pathway-biased agonist DOI-NBOMe has an effective and long-term therapeutic effect in a mouse model of depressive-like behavior and does not produce hallucination-like side effects.

[0039] To evaluate whether DOI-NBOMe has a therapeutic effect on the anxiety / obsessive-compulsive symptoms of mental disorders, we conducted a marble-burying test 30 minutes after drug administration. Mice showed a decrease in marble burying in the DOI or DOI-NBOMe treatment (as Figure 6 shown in a). When the mice were tested again 24 hours after drug administration, the DOI-treated mouse group had an increase in marble burying. In contrast, the mice treated with DOI-NBOMe maintained a decrease in marble burying (as Figure 6 shown in b). These results demonstrate that DOI-NBOMe has a therapeutic effect on anxiety / obsessive-compulsive mental disorders.

[0040] As can be seen from the above results, compared with the depressive model mice, after treatment with DOI-NBOMe, the depressive behavior of the mice was significantly improved and the immobility time was reduced. Compared with the mice treated with Fluoxetine, the depressive behavior of the mice treated with DOI-NBOMe could be improved more rapidly and had a long-term antidepressant effect. In the anxiety / obsessive-compulsive mice, the mice treated with DOI-NBOMe tended to normalize and could achieve the purpose of treating anxiety / obsessive-compulsive disorder. The selective 5-HT 2A R-biased agonist DOI-NBOMe has a significant effect in the treatment of mental disorders and has the prospect of practical popularization and application. And compared with the existing compounds with improved depressive behavior such as DOI and NBOMes, it does not have hallucination-like side effects.

Claims

1. A selective 5-HT 2A The use of an R-biased agonist in the preparation of a drug for treating mental disorders is characterized in that: The selective 5-HT 2A R-biased agonists selectively target 5-HT 2A R's bias towards G q Agonists of signaling pathway activity.

2. A selective 5-HT according to claim 1 2A Application of a selective 5-HT R-biased agonist in the preparation of a drug for treating mental disorders, wherein the selective 5-HT 2A R-biased agonists are:

3. A selective 5-HT according to claim 1 2A The invention relates to the use of an R-biased agonist in the preparation of a drug for treating mental disorders, wherein the mental disorders include depression, schizophrenia, obsessive-compulsive disorder and anxiety disorder.

4. A composition for preparing a drug for treating mental disorders, characterized in that: The composition comprises the selective 5-HT as claimed in any one of claims 1 to 3 2A R-biased agonist and pharmaceutically acceptable excipients.

5. A composition for preparing a drug for treating mental disorders according to claim 4, characterized in that: The auxiliary materials include excipients and additives.

6. A composition for preparing a drug for treating mental disorders according to claim 5, characterized in that: The mental disorders include depression, schizophrenia, obsessive-compulsive disorder, and anxiety disorder.

7. A composition for preparing a drug for treating mental disorders according to claim 4, characterized in that: The selective 5-HT 2A R-biased agonists are:

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