Application of carboline compound in preparation of antidepressant drug

Abstract

The invention belongs to the technical field of biomedicine, and particularly relates to application of carboline compounds in preparation of antidepressant drugs. According to the present invention, the carboline compound or the pharmaceutically acceptable salt thereof can target the 5-HT2A receptor, and has the 5-HT2A receptor excitation activity; the compound can effectively relieve depression symptoms of mice in a mouse spontaneous activity experiment model, a tail suspension experiment model and an open field experiment model under the dosage of 10 mg / kg-20 mg / kg. As an anti-depression drug, compared with an existing 5-HT2A agonist, the compound has a relatively strong anti-depression effect, but the carboline compound does not have a magical effect and has a prospect of being developed into an anti-depression treatment drug.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of biomedical technology, and particularly relates to application of a compound of the carboline type in preparation of an antidepressant. BACKGROUND

[0002] The core symptoms of depression are manifested as low mood, slow thinking and reduced will activity, often accompanied by cognitive impairment and somatization symptoms such as sleep disorders, pain, etc., which seriously affect the normal work and life of patients, increase the economic burden of patients, and the disease has become a major public health problem.

[0003] Currently, the widely used antidepressants are mainly based on the monoamine neurotransmitter hypothesis, and play a therapeutic role by regulating the 5-hydroxytryptamine (5-HT), norepinephrine and dopamine systems. According to the different mechanisms of action, the existing drugs can be divided into five categories: (1) tricyclic antidepressants; (2) monoamine oxidase inhibitors; (3) selective serotonin reuptake inhibitors (SSRIs); (4) serotonin and norepinephrine reuptake inhibitors (SNRIs); (5) atypical antidepressants, etc.

[0004] Antidepressants play an important role in the treatment of depression, but the side effects are still an important challenge in the field of psychiatry. Tricyclic antidepressants often have anticholinergic side effects such as dry mouth, constipation, blurred vision, urinary retention, facial flushing, etc., and may also have symptoms such as drowsiness, tremor, confusion, seizures, hallucinations, orthostatic hypotension, tachycardia, arrhythmia, etc. Monoamine oxidase inhibitors may cause hypertensive crisis, 5-HT syndrome, nausea, vomiting, arrhythmia, etc. Common side effects of SSRIs and SNRIs include nausea, diarrhea, insomnia, drowsiness, headache, sexual dysfunction, etc. Atypical antidepressants may cause drowsiness, weight gain, nausea and headache, etc. Studies have shown that most antidepressants may produce some initial improvement within the first two weeks of treatment, but complete efficacy usually takes 2-3 weeks or even longer, and the success rate of treatment is low. In addition, new antidepressants such as ketamine and related molecules have shown potential in rapid onset, but have side effects such as neurotoxicity, cognitive impairment and addiction, which seriously affect the treatment compliance and quality of life of patients. Therefore, the development of new antidepressants with rapid onset and low side effects has become a core goal in the field of psychiatry and drug research and development.

[0005] 5-hydroxytryptaime 2A receptor (5-HT 2A R) is involved in the pathological process of mental diseases such as depression by mediating neural plasticity and synaptic remodeling mechanisms. 5-HT 2A R also plays a core regulatory role in key physiological processes such as dynamic regulation of neural plasticity, maintenance of emotional homeostasis, and reconstruction of synaptic microenvironment. It has been reported that agonists targeting this receptor, such as psilocybin (Pcb), have rapid and long-acting antidepressant effects, but their hallucinogenic side effects limit their clinical application. Therefore, it is of great significance to screen a non-hallucinogenic agonist targeting 5-HT 2A R that can exert good efficacy while reducing side effects for the development of new antidepressants.

[0006] β-carboline compounds exert antidepressant effects by activating 5-HT 2A R, can overcome the delayed effect of traditional antidepressants (such as SSRIs which take several weeks to take effect), and have no hallucinogenic effect, and are a novel class of antidepressant compounds. SUMMARY

[0007] The purpose of the present application is to provide a carboline compound with 5-HT 2A receptor agonistic activity and an antidepressant effect, and its application. The compound in the present application has obvious agonistic effect on 5-HT 2A R, has obvious antidepressant effect, and has no hallucinogenic effect, and has the potential to be developed as an antidepressant.

[0008] The present application is realized by the following technical solutions.

[0009] In a first aspect, the present application provides the use of a carboline compound in the preparation of an antidepressant, wherein the compound is a compound of the following formula I or a pharmaceutically acceptable salt thereof:

[0010]

[0011] R1, R2, R3 in formula I are independent of each other;

[0012] R1 is selected from H, a halogen atom, a cycloalkane of 3-8 C;

[0013] R2 is selected from H, a halogen atom;

[0014] R3 is selected from an alkoxy group of 1-3 C.

[0015] Preferably, the compound is a carboline compound of HTA, HTB, HTC, HTD, THE, which has 5-HT 2AThe receptor agonist activity has an antidepressant effect.

[0016] Table 1. Compounds of the carboline class

[0017]

[0018] In a second aspect, the present application provides a pharmaceutical composition comprising the compound according to the first aspect or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0019] Preferably, the pharmaceutically acceptable carriers, diluents or excipients include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycol.

[0020] Preferably, the pharmaceutical composition is administered orally or by injection.

[0021] Further, the active ingredient is administered at a dose of 10 mg / kg to 20 mg / kg.

[0022] Preferably, the pharmaceutical composition is a tablet, capsule, solution, suspension or injection.

[0023] Advantages of the present application:

[0024] The present application provides a use of a compound of the carboline class in the preparation of an antidepressant drug, which is a 5-HT2 A receptor agonist, and has a significant agonist effect on 5-HT 2A receptors. The compound can effectively reduce or eliminate the depressive symptoms of mice in the spontaneous activity test model, tail suspension test model and open field test model, and can be used as an antidepressant drug. The compound has a strong antidepressant effect and no hallucinogenic effect, and is a novel antidepressant compound with the potential to develop into an antidepressant drug. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 The figure shows the agonist dose-effect relationship of the control compound Pcb on 5-HT 2A receptors.

[0026] Figure 2 The figure shows the agonist activity of the control compound Pcb and the representative compound of the carboline class according to the present application on 5-HT 2A receptors.

[0027] Figure 3 The figure shows the agonist dose-effect relationship of the HTC according to the present application on 5-HT 2A receptors.

[0028] Figure 4 Figure 4 shows a graph of the body weight change of a depression model mouse prepared for 21 days.

[0029] Figure 5 Figure 5 shows a graph of a depression model mouse evaluated by a tail suspension test.

[0030] Figure 6 Figure 6 shows a graph of a depression model mouse evaluated by a mine field test.

[0031] Figure 7 Figure 7 shows a graph of a depression model mouse evaluated by a forced swimming test.

[0032] Figure 8 Figure 8 shows a graph of the anti-depression activity of HTA, HTC and HTD on mice evaluated by a spontaneous activity test.

[0033] Figure 9 Figure 9 shows a graph of the anti-depression activity of different doses of HTC compound on mice evaluated by a spontaneous activity test.

[0034] Figure 10 Figure 10 shows a graph of the anti-depression activity of HTA, HTC and HTD on mice evaluated by a tail suspension test.

[0035] Figure 11 Figure 11 shows a graph of the anti-depression activity of different doses of HTC compound on mice evaluated by a tail suspension test.

[0036] Figure 12 Figure 12 shows a graph of the anti-depression activity of HTA, HTC and HTD on mice evaluated by a mine field test.

[0037] Figure 13 Figure 13 shows a graph of the anti-depression activity of different doses of HTC compound on mice evaluated by a mine field test. DETAILED DESCRIPTION

[0038] The specific embodiments of the present application will be described in detail below with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative and explanatory and are not intended to limit the present application.

[0039] The compound described in the present application is not particularly limited, and can be prepared by those skilled in the art according to the common knowledge in the art, or obtained by being commercially available.

[0040] The present application will be described in detail below through examples.

[0041] In the following examples, the various reagents and materials used are commercially available unless otherwise specified.

[0042] In the following examples, the compound is 5-HT2A The agonistic effect of the receptor was detected by the FLIPR instrument. The FLIPR detection method is a homogeneous, dynamic, fluorescence detection method at the cellular level. When the cell line expressing the 5-HT 2A receptor is incubated with a calcium-sensitive fluorescent dye, the dye enters the cells. When a compound with 5-HT 2A receptor agonistic activity binds to the 5-HT 2A receptor on the cell surface, it can cause a change in the intracellular calcium ion concentration, and then cause a change in the fluorescence signal of the calcium-sensitive fluorescent dye. According to the change of the fluorescence signal, the agonistic activity of the compound on the 5-HT 2A receptor can be detected in real time.

[0043] In the following examples, corticosterone (CORT) was used instead of drinking water to feed mice for 21 days to construct an animal depression model. The tail suspension test (TST), open field test (OFT), and forced swim test (FST) were used to confirm the successful construction of the depression model. The spontaneous activity test (SAT), TST, and OFT were used to test the antidepressant effect of the compound.

[0044] In the following examples, the experimental C57 BL / 6J mice used were all purchased from Beijing Huafukang Biotechnology Co., Ltd., license number: SCXK (Beijing) 2019-0008, male, body weight 18-22 g, and mouse age 8 weeks.

[0045] Example 1: Agonist dose-response relationship of the control compound Pcb to 5-HT 2A receptor.

[0046] The 5-HT 2A R stably transfected 5-HT 2A R-CHO cells were seeded into a 384-well black-bottom transparent culture plate at 10,000 cells / well, and 20 μL of medium was added to each well. The cells were cultured at 37 °C under 5% CO2 for 24 h. When the cell confluence in the wells reached 80%, the medium in the wells was removed, and 20 μL of FLIPR calcium flux detection fluorescent dye was added to each well. The cells were incubated for 1 h at 37 °C in the dark.

[0047] Psilocybin (Pcb) is an antidepressant compound known to have 5-HT 2A R agonistic activity. In this example, it was used as a positive control compound to evaluate the 5-HT 2APharmacological function of R-CHO cells. Freshly prepared serially diluted Pcb was added to compound plates (maximum concentration 18 μmol / L, serially diluted 3-fold, for a total of 8 concentrations, with 3 replicates for each concentration). Different concentrations of Pcb were added to 384-well cell plates using a FLIPR automated sample loading system and incubated for 20 min. Fluorescence was read according to the parameter settings: excitation wavelength 470–495 nm, emission wavelength 515–575 nm, exposure time 0.2 s, data collected once per second for 120 s. The changes in fluorescence signal over time caused by different concentrations of Pcb were detected by real-time sample loading and recording.

[0048] according to Figure 1 Different concentrations of Pcb induced S-shaped curves in the fluorescence signal, exhibiting a clear dose-response relationship. Pcb also affected 5-HT... 2A R cell agonistic effect EC 50 The value is 0.83 μmol·L⁻¹. These results indicate that 5-HT… 2A The R-cell model can well reflect the effect of compounds on 5-HT. 2A The agonistic effect of R is applicable to the reaction of compounds with 5-HT. 2A Evaluation of the in vitro activity of R-agonists.

[0049] Example 2: Positive control compound Pcb and carboline compounds of the present invention on 5-HT 2A The agonistic activity of receptors.

[0050] Stable transfection with 5-HT 2A R's 5-HT 2A R-CHO cells were seeded at 10,000 cells / well in 384-well black-bottomed permeable culture plates, with 20 μL of culture medium added to each well. The plates were incubated at 37°C and 5% CO2 for 24 h. When the cell confluence reached 80%, the culture medium was removed, and 20 μL of FLIPR calcium flux detection fluorescent dye was added to each well. The plates were then incubated at 37°C in the dark for 1 h.

[0051] Freshly prepared Pcb and carboline compounds were added to compound plates (Pcb concentration 1 μmol·L⁻¹, carboline compound concentration 10 μmol·L⁻¹), with three replicate wells for each compound. Using a FLIPR automated sample loading system, Pcb and carboline compounds were added to 384-well cell culture plates and incubated for 20 min. Fluorescence was then read according to the parameters set: excitation wavelength 470–495 nm, emission wavelength 515–575 nm, exposure time 0.2 s, and data collected once per second for 120 s. Real-time sample loading and recording were used to detect changes in fluorescence signals induced by Pcb and carboline compounds.

[0052] according to Figure 2 With Pcb causing a 100% change in fluorescence signal, the percentage changes in fluorescence signal caused by carboline compounds HTA, HTB, HTC, HTD, and HTE were 164.18%, 88.31%, 39.95%, 177.13%, and 112.15% of that caused by Pcb, respectively. Among these, HTC significantly affected 5-HT... 2A R cells exhibit the greatest agonistic effect.

[0053] Example 3: Compound HTC [1-{3-[(4-fluorophenoxy)methyl]-4-methoxyphenyl}-2,3,4-9-tetrahydro-1H-β-carbazoline] for 5-HT 2A The agonist dose-effect relationship of receptors.

[0054] Stable transfection with 5-HT 2A R's 5-HT 2A R-CHO cells were seeded at 10,000 cells / well in 384-well black-bottomed permeable culture plates, with 20 μL of culture medium added to each well. The plates were incubated at 37°C and 5% CO2 for 24 h. When the cell confluence reached 80%, the culture medium was removed, and 20 μL of FLIPR calcium flux detection fluorescent dye was added to each well. The plates were then incubated at 37°C in the dark for 1 h.

[0055] Freshly prepared serially diluted HTC was added to the well plates (maximum concentration 100 μmol / L, serially diluted 3-fold to a total of 12 concentrations, with 3 replicates for each concentration). Using a FLIPR automated loading system, different concentrations of HTC were added to the 384-well cell culture plates and incubated for 20 min. Fluorescence was then read according to the parameters set: excitation wavelength 470–495 nm, emission wavelength 515–575 nm, exposure time 0.2 s, data collected once per second for 120 s. Real-time loading and recording were used to detect changes in fluorescence signal over time caused by different concentrations of HTC.

[0056] according to Figure 3 The fluorescence signal changes induced by different concentrations of HTC exhibited an "S"-shaped curve, with a clear dose-response relationship. HTC affects 5-HT... 2A R cell agonistic effect EC 50 A value of 0.58 μmol / L indicates that HTC is 5-HT. 2A R agonist, and 5-HT 2A R exhibits good agonistic activity.

[0057] Example 4: Weight changes of model mice over 21 days.

[0058] CORT powder was dissolved in 10 mL of absolute ethanol and ultrasonicated for 5-10 minutes until completely dissolved, and then diluted with 990 mL of drinking water to 0.1 mg / mL. The solution was prepared daily and used immediately, and the CORT solution was replaced every day for 21 consecutive days. During the modeling period, the body weight of the mice was measured every 7 days. Eight mice in the Con group and 72 mice in the Model group were set up in the experiment, and 8 mice in the Model group were randomly selected to monitor the body weight. As shown in Figure 4 The body weight of the mice in the Con group increased steadily, while the body weight of the mice in the Model group increased slowly, which was consistent with the clinical manifestations of decreased appetite and weight loss commonly seen in patients with depression. At different time points (7th day, 14th day and 21st day), the difference in body weight between the two groups was statistically significant (p<0.05, p<0.0001). Compared with the Con group, the body weight of the mice in the Model group decreased by 11.83%, 11.46% and 7.38% on the 7th day, 14th day and 21st day, respectively, confirming that the 0.1 mg / mL CORT replacement drinking water modeling had a significant effect on the body weight gain of the mice. Body weight change is an important indicator for evaluating the effectiveness of the depression model. The body weight gain difference shown in the figure is consistent with the characteristics of the mouse depression model.

[0059] Example 5: Evaluation of mouse depression model by tail suspension test

[0060] Construction of mouse depression model: 100 mg of CORT powder was dissolved in 10 mL of absolute ethanol and ultrasonicated for 5-10 minutes until completely dissolved, and then diluted with 990 mL of drinking water to 0.1 mg / mL. The solution was prepared daily and used immediately, and the CORT solution was replaced every day for 21 consecutive days. Eight mice in the Con group and 72 mice in the Model group were set up in the experiment.

[0061] Evaluation of mouse depression model by TST experiment: After 21 days of modeling, the TST experiment was used to evaluate the depression model of the mice. A single mouse was fixed on the top bracket of the tail suspension box about 1-2 cm from the tail tip with medical tape, so that the mouse was in an inverted state with the head about 5 cm from the bottom of the box. The immobile time in the last 4 minutes was recorded and calculated. The results of the TST experiment after modeling (21st day) are shown in Figure 5 As shown in the figure, compared with the Con group, the immobile time of the mice in the Model group increased by 8.22% (p<0.001) in the TST experiment, showing a significant difference. Therefore, the 0.1 mg / mL CORT replacement drinking water mouse depression model was successfully constructed.

[0062] Example 6: Evaluation of mouse depression model by mine field test

[0063] Construction of mouse depression model: 100 mg CORT powder was dissolved in 10 mL of absolute ethanol, ultrasonic for 5-10 minutes to completely dissolved, and then diluted with 990 mL of drinking water to 0.1 mg / mL. The solution was prepared daily and used, and the CORT solution was replaced once a day for 21 consecutive days. Eight mice in the Con group and 72 mice in the Model group were set up in the experiment.

[0064] Evaluation of mouse depression model by OFT experiment: After 21 days of modeling, the depression model of mice was evaluated by OFT experiment. The mice were placed in the open field box and the automatic observation and analysis imaging system was used to observe the activity of the mice in 5 minutes. The bottom of the open field box (4 cm x 44 cm x 44 cm) was divided into 16 equal squares, and the middle 4 squares were the center area and the other squares were the edge area. Each mouse was placed in the center area of the open field box (the bottom was white), and the VisuTrack rodent behavior video analysis software version 3.0 was used to analyze the immobility time of the mice in 5 minutes. The results are shown in Figure 6 Compared with the Con group, the immobility time of the mice in the Model group in the OFT experiment increased by 29.48% (p<0.01), showing a significant difference. Therefore, the mouse depression model was successfully constructed by replacing drinking water with 0.1 mg / mL CORT.

[0065] Example 7: Evaluation of mouse depression model by forced swimming test.

[0066] Construction of mouse depression model: 100 mg CORT powder was dissolved in 10 mL of absolute ethanol, ultrasonic for 5-10 minutes to completely dissolved, and then diluted with 990 mL of drinking water to 0.1 mg / mL. The solution was prepared daily and used, and the CORT solution was replaced once a day for 21 consecutive days. Eight mice in the Con group and 72 mice in the Model group were set up in the experiment.

[0067] Evaluation of mouse depression model by FST experiment: After 21 days of modeling, the depression model of mice was evaluated by FST experiment. The FST real-time monitor was used for testing, and each mouse was placed in a transparent glass jar (diameter 15 cm, height 22 cm) with water temperature of 24°C and water depth of 16 cm. The immobility time of the mice in the last 4 minutes was recorded continuously for 6 minutes. The results are shown in Figure 7 Compared with the Con group, the immobility time of the mice in the Model group in the FST experiment increased by 41.35% (p<0.001), showing a significant difference. Therefore, the mouse depression model was successfully constructed by replacing drinking water with 0.1 mg / mL CORT.

[0068] Example 8: Evaluation of the anti-depression effect of HTA, HTC and HTD on mice by spontaneous activity experiment.

[0069] The mice with depressive symptoms evaluated by TST, OFT and FST experiments were randomly divided into groups, each group containing 8 mice, and divided into Model group (solvent composed of 5% DMSO: 45% PEG400: 5% Tween80: 45% normal saline), positive control group (Pcb, 1 mg / kg), 3 compound groups (HTA, HTC, HTD, 10 mg / kg), all groups were administered by intraperitoneal injection, the intraperitoneal injection volume was 20 μL / 100 g body weight. The anti-depression effect of the compounds was evaluated by SAT experiment 1 h after administration. The fine activity of the mice was monitored and recorded by Laboras system. The mice were placed in the SAT experiment cage, free water, and the behavior activity of the mice was monitored and recorded within 10 min. As shown in Figure 8 compared with the Model group, the SAT immobility time of the HTA group, HTC group and HTD group was significantly reduced (p<0.01, p<0.0001). The three compounds at a dose of 10 mg / kg were basically comparable to the activity of Pcb (p>0.05), showing similar anti-depression activity. Compared with the positive drug Pcb group, the anti-depression activity of HTA, HTC and HTD was 95.66%, 102.92% and 91.88% of Pcb respectively, showing obvious anti-depression activity.

[0070] Example 9: Evaluation of the anti-depression effect of different doses of HTC on mice by spontaneous activity experiment.

[0071] The mice with depressive symptoms evaluated by TST, OFT and FST experiments were randomly divided into groups, each group containing 8 mice, and divided into Model group (solvent composed of 5% DMSO: 45% PEG400: 5% Tween80: 45% normal saline), positive control group (Pcb, 1 mg / kg), 3 compound groups (HTA, HTC, HTD, 10 mg / kg), all groups were administered by intraperitoneal injection, the intraperitoneal injection volume was 20 μL / 100 g body weight. The anti-depression effect of the compounds was evaluated by SAT experiment 1 h after administration. The fine activity of the mice was monitored and recorded by Laboras system. The mice were placed in the SAT experiment cage, free water, and the behavior activity of the mice was monitored and recorded within 10 min. As shown in Figure 9The immobility time in the SAT of the HTC at the doses of 10 and 20 mg / kg was significantly reduced compared with the Model group (p<0.001, p<0.0001), indicating that the HTC at the doses of 10 and 20 mg / kg had obvious antidepressant effects. The immobility time in the SAT of the 20 mg / kg dose group of the HTC was significantly reduced compared with the 10 mg / kg dose group of the HTC (p<0.05), indicating that the antidepressant activity of the HTC was dose-dependent. The 20 mg / kg dose of the HTC showed a stronger antidepressant effect than the Pcb, and the activity was increased by 25.27% (p<0.05). This indicated that the 20 mg / kg dose group of the HTC had obvious antidepressant effects.

[0072] Example 10: Evaluation of the antidepressant effects of HTA, HTC and HTD on mice using the tail suspension test.

[0073] The mice with depressive symptoms evaluated by the TST, OFT and FST experiments were randomly divided into groups, each containing 8 mice, and were divided into a Model group (solvent composed of 5% DMSO: 45% PEG400: 5% Tween80: 45% normal saline), a positive control group (Pcb, 1 mg / kg), and three compound groups (HTA, HTC, HTD, 10 mg / kg). All groups were administered by intraperitoneal injection, with an intraperitoneal injection volume of 20 μL / 100 g of body weight. The antidepressant effects of the compounds were evaluated using the TST experiment 2 h after administration. The mice were fixed on the tail suspension tester with their heads suspended, and the immobility time was recorded continuously for 6 min. The immobility time of each compound group (Pcb at 1 mg / kg, and HTA, HTC and HTD at 10 mg / kg) was compared with that of the Model group. The results are shown in Table 1. Figure 10 The TST immobility time of the mice in the Pcb group was significantly reduced compared with the Model group (p<0.001), indicating that the Pcb had obvious antidepressant effects. The TST immobility time of the mice in the HTA, HTC and HTD groups was significantly reduced compared with the Model group (p<0.01, p<0.0001). The three compounds at the dose of 10 mg / kg had basically the same activity as the Pcb (p>0.05), showing similar antidepressant activities. The antidepressant activities of the HTA, HTC and HTD were 99.22%, 97.76% and 97.64% of that of the Pcb, respectively, compared with the positive drug Pcb group, and they had obvious antidepressant activities.

[0074] Example 11: Evaluation of the antidepressant effects of different doses of HTC on mice using the tail suspension test.

[0075] The mice with depressive symptoms evaluated by TST, OFT and FST experiments were randomly divided into groups, each group containing 8 mice, and were divided into Model group (solvent composed of 5% DMSO: 45% PEG400: 5% Tween80: 45% normal saline), positive control group (Pcb, 1 mg / kg), HTC compound group 2 (10, 20 mg / kg), all groups were administered by intraperitoneal injection, the intraperitoneal injection volume was 20 μL / 100 g body weight. The anti-depression effect of the compound was evaluated by TST experiment 2 h after administration. The mouse tail was fixed on the tail suspension test instrument, the head was suspended, and the immobile time in the last 4 min was recorded continuously for 6 min. The immobile time of each dose group of HTC was compared with the model group. The results are shown in Figure 11 Compared with the Model group, HTC at a dose of 10, 20 mg / kg significantly reduced the immobile time in TST (p<0.01, p<0.0001), indicating that each administration group of HTC had obvious anti-depression effect. Compared with the 10 mg / kg HTC dose group, the immobile time in TST was significantly reduced (p<0.01) in the 20 mg / kg HTC dose group, indicating that the anti-depression activity of HTC was dose-dependent. Compared with Pcb, 20 mg / kg dose of HTC showed stronger anti-depression effect, and the activity increased by 5.06% (p<0.05). It is shown that 20 mg / kg HTC has obvious anti-depression effect.

[0076] Example 12: Evaluation of the anti-depression effect of HTA, HTC and HTD on mice by open field experiment.

[0077] The mice with depressive symptoms evaluated by TST, OFT and FST experiments were randomly divided into groups, each group containing 8 mice, and were divided into Model group (solvent composed of 5% DMSO: 45% PEG400: 5% Tween80: 45% normal saline), positive control group (Pcb, 1 mg / kg), compound group 3 (HTA, HTC, HTD, 10 mg / kg), all groups were administered by intraperitoneal injection, the intraperitoneal injection volume was 20 μL / 100 g body weight. The anti-depression effect of the compound was evaluated by OFT experiment 4 h after administration. The mouse was placed in the open field box, and the activity of the mouse in 5 min was observed by automatic observation and analysis imaging system. The number of central crossings of mice in each compound group (Pcb was 1 mg / kg, and different doses of HTE were 10, 20, 30 mg / kg) and the model group was compared to evaluate the dose-effect relationship of HTE anti-depression. The results are shown in Figure 12Compared with the Model group, the number of central shuttling of the mice in the Pcb group was significantly increased (p<0.01), indicating that Pcb had a significant antidepressant effect. Compared with the Model group, the number of central shuttling of the mice in the HTA, HTC and HTD groups was significantly increased (p<0.01), which was basically equivalent to the activity of Pcb at a dose of 1 mg / kg (p>0.05). Compared with the positive drug Pcb group, the antidepressant activity of the HTA, HTC and HTD groups was 98.73%, 101.27% and 80% of that of Pcb, respectively, and had obvious antidepressant activity.

[0078] Example 13: Evaluation of the antidepressant effect of different doses of HTC on mice by using the open field test.

[0079] The mice with depressive symptoms evaluated by the TST, OFT and FST experiments were randomly divided into groups, each group containing 8 mice, and were divided into a Model group (solvent composed of 5% DMSO: 45% PEG400: 5% Tween80: 45% normal saline), a positive control group (Pcb, 1 mg / kg), two HTC compound groups (10 and 20 mg / kg), all of which were administered by intraperitoneal injection, with an intraperitoneal injection volume of 20 μL / 100 g of body weight. The antidepressant effect of the compounds was evaluated by the OFT experiment 4 h after administration. The mice were placed in the open field box and the activity of the mice in 5 min was observed by using an automatic observation and analysis imaging system. The results are shown in Figure 13 Compared with the Model group, the number of central shuttling of the mice in the Pcb group was significantly increased (p<0.01), indicating that Pcb had a significant antidepressant effect. Compared with the Model group, the number of central shuttling of the mice in the HTA, HTC and HTD groups was significantly increased (p<0.01), which was basically equivalent to the activity of Pcb at a dose of 1 mg / kg (p>0.05). Compared with the positive drug Pcb group, the antidepressant activity of the HTA, HTC and HTD groups was 98.73%, 101.27% and 80% of that of Pcb, respectively, and had obvious antidepressant activity.

[0080] From the results of the above examples, it can be seen that the carboline compound of the present application has a significant agonistic effect on 5-HT 2A receptors, and can significantly improve the depressive symptoms of the mouse depression model prepared by CORT, and no hallucinogenic effect is found. The success of the depression model is confirmed by the TST experiment and the SAT experiment, and the HTE has a significant antidepressant effect, which is confirmed by the TST, OFT open field experiment and FST experiment. The carboline compound of the present application can be applied to the preparation of a drug for preventing or treating depression.

Claims

1. The use of a carboline compound in the preparation of antidepressant drugs, characterized in that, The compound is a compound of the following formula I or a pharmaceutically acceptable salt thereof: R1, R2, R3 in formula I are independent of each other; R1 is selected from H, halogen atom, cycloalkane of 3-8 C; R2 is selected from H, halogen atom; R3 is selected from alkoxy of 1-3 C.

2. Use of a compound according to claim 1 for the preparation of a medicament for the treatment of depression, characterized in that, The compound is HTA-HTE, and the structural formula is:

3. A pharmaceutical composition, characterized by, The compound is a compound of the following formula I or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition of claim 3, wherein, The pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents or excipients.

5. The pharmaceutical composition of claim 4, wherein The pharmaceutically acceptable carriers, diluents or excipients include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycol.

6. The pharmaceutical composition of claim 3, wherein, The pharmaceutical composition is administered orally or by injection.

7. The pharmaceutical composition of claim 3, wherein, The dose of the active ingredient is 10 mg / kg to 20 mg / kg.

8. The pharmaceutical composition of claim 3, wherein, The pharmaceutical composition is a tablet, capsule, solution, suspension or injection.

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