CN114652720B

CN114652720B - Application of epilupine and derivatives thereof in preparation of medicines for treating depression

Info

Publication number: CN114652720B
Application number: CN202210161755.4A
Authority: CN
Inventors: 杜静; 吉腾飞; 阚伟京; 王刚
Original assignee: Institute of Materia Medica of CAMS; Beijing Anding Hospital
Current assignee: Institute of Materia Medica of CAMS; Beijing Anding Hospital
Priority date: 2022-02-22
Filing date: 2022-02-22
Publication date: 2023-05-09
Anticipated expiration: 2042-02-22
Also published as: CN114652720A

Abstract

The invention provides application of epilupine (1-epilupine) and derivatives thereof in preparing a medicament for treating depression. The application dosage is 0.01-30mg of epilupine or its derivative per kg of body weight, and the antidepressant effect can be produced within 60 minutes after administration. After 5 days of administration, both low and high doses produced significant antidepressant effects. The research result of the invention shows that in the tail suspension experiment of the mammal and the mouse, the epilupine or the derivative thereof has the effect of rapidly resisting depression and is more effective than the conventional antidepressant imipramine. The invention adopts a forced swimming experiment and a mouse tail suspension experiment as drug screening experiments, and simultaneously carries out a mouse Open field experiment (Open field test) so as to test the autonomous activity of the mice and avoid the interference of central stimulants. The antidepressant has the advantages of remarkable antidepressant effect, quick response, small dosage, small side effect and the like, and is expected to become a novel antidepressant with quick, efficient and novel mechanism.

Description

Application of epilupine and derivatives thereof in preparation of medicines for treating depression

Technical Field

The invention belongs to the technical field of medicines, and relates to application of epilupine (1-EPILUPINE) and derivatives thereof in preparation of medicines for treating depression and antidepressant medicines prepared from the epilupine (1-EPILUPINE).

Background

Major depressive disorder (Major depressive disorder, MDD) is a serious, recurrent disabling mental disorder, and is a worldwide population with about 3 million depressive patients. The incidence rate of the Chinese depression is 4.2%, and about 5600 ten thousand patients suffering from the depression exist. Depression is the second leading cause of life loss (years) from injury and has become a major public health problem that needs to be addressed urgently. Depression is clinically seen as depression with mood down, spell depression, even pessimistic aversion, suicidal attempts or behaviors. The prior clinical first-line antidepressant mainly comprises a selective 5-hydroxytryptamine reuptake inhibitor, a norepinephrine reuptake inhibitor and the like, but the medicament has slow effect and narrow action spectrum, and is easy to relapse after stopping the medicament. Although treated with a variety of antidepressants, about 30% of patients become refractory to depression (treatent-resistant Depression, TRD). Such refractory depression patients present a higher risk of social burden and suicide. Therefore, finding new antidepressant drugs with good compliance, few side effects and novel pharmacological mechanisms has great clinical demands, and is also a hotspot of current international research.

Epilupine (1-epilupine), also known as epilupine, is isolated from lupin (Lupinus polyphyllus) which is a plant of the genus lupin of the family Leguminosae. Epilupine is a quinolone alkaloid component with molecular formula of C ₁₀ H ₁₉ NO, molecular weight 169.26, melting point 77-78deg.C, is dissolved in chloroform, methanol, ethanol. Can be used for preparing chemical pesticide.

Sub-acute toxicity experiments prove that the epilupine has no obvious influence on the functions of bone marrow, liver, kidney and the like of rats. No report of the prevention or treatment of depression by using epilupin as an active ingredient is currently seen.

Disclosure of Invention

The invention aims to provide an application of epilupin alkaloid and derivatives thereof in preparing a medicament for treating depression, and the medicament has the advantages of remarkable anti-depression effect, quick response, small dosage, small side effect and the like.

The invention provides application of lupin alkaloid or derivatives thereof in preparing medicines for treating depression,

further, the derivative includes: an organic acid/inorganic acid salt type product of lupin base, and an esterification product or an etherification product of the hydroxyl group at the 11-position.

Further, the application dose is 0.01-30mg of epilupine or its derivative per kg of body weight.

The invention also provides an antidepressant, which comprises the following components: epilupine or a derivative thereof, and pharmaceutically acceptable auxiliary ingredients.

The pharmaceutical compositions also include pharmaceutical compositions that have a positive effect on the treatment of depression following simultaneous administration.

Further, the pharmaceutical components having positive effects on treating depression after the simultaneous administration are: monoamine oxidase inhibitors MAOI, tricyclic antidepressants TCA, selective serotonin reuptake inhibitors SSRI, serotonin and norepinephrine reuptake inhibitors SNRI, noradrenergic and specific 5-HT receptor antagonists NASSA, 5-HT antagonist and reuptake inhibitors, or melatonin and 5-HT2C receptor antagonists.

Further, the tricyclic antidepressants (TCA) include amitriptyline, promazine, chlorpromazine, doxepin, clomipramine, and the like; the Selective Serotonin Reuptake Inhibitor (SSRI) is for example: fluoxetine (paradox), paroxetine (selet), fluvoxamine (blue), sertraline (sertraline, zuo Luofu), citalopram (citalopram), escitalopram (lescitalopram), and the like; such Serotonin and Norepinephrine Reuptake Inhibitors (SNRI), e.g., venlafaxine, duloxetine, and the like; the noradrenergic and specific 5-HT receptor antagonists (NASSA), such as mirtazapine and the like; the 5-HT antagonism and reuptake inhibitor: such as nefazodone and trazodone; the melatonin and 5-HT2C receptor antagonist: such as agomelatine.

Further, the pharmaceutical ingredients having positive effects on the treatment of depression after the simultaneous administration are herbs such as: san jojose, (st. Jonh's work) and tenectepstein, vortioxetine (also known as Vortioxetine), bupropion (Bupropion), and the like.

Further, the pharmaceutical components having positive effects on treating depression after the simultaneous administration are: ketamine, including S-ketamine or ketamine nasal feeds.

Further, the effective dosage of the medicine is 0.01-30mg of epilupine and derivatives thereof per kilogram of body weight.

The medicine is in the form of powder, granule, tablet, capsule, pill, solution, suspension or injection.

The epilupine is white powder, HRESI-MS M/z [ M+H ]] ⁺ 170.1539 it is suggested that its molecular formula is C ₁₀ H ₁₉ NO。

¹ H NMR(400MHz,CDCl ₃ )δ3.73-3.46(m,1H),2.86-2.68(m,1H),2.01(ddd,J＝14.6,11.4,2.9Hz,1H),1.92-1.79(m,1H),1.79–1.63(m,1H),1.59(t,J＝3.4Hz,1H),1.51-1.35(m,OH),1.30-1.09(m,1H).

¹³ C NMR(100MHz,CDCl ₃ )δ64.67,64.31,56.92,56.64,43.96,29.78,28.23,25.60,25.04,24.58。

The medicament of the invention can be administered in unit dosage form, and the administration dosage form can be liquid dosage form or solid dosage form. For example, the liquid dosage form may be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.

The route of administration may be enteral or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosal, dermal, peritoneal or rectal, etc.

The route of administration of the medicament of the invention may be injection. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection, etc.

The medicine of the invention can be prepared into common preparations, sustained release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.

For the purpose of shaping the unit dosage form into a tablet, various carriers known in the art can be widely used. In the carrier: diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, etc.; wetting agents and binders such as water, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, dextrose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, and the like; disintegrants such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose, ethylcellulose, and the like; disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oils and the like; absorption promoters such as quaternary ammonium salts, sodium lauryl sulfate, and the like; lubricants such as talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or double and multi layered tablets.

For the preparation of the dosage unit into a pill, various carriers well known in the art can be widely used. In the carrier: such as diluents and absorbents like glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, polyvinylpyrrolidone, gelucire, kaolin, talc, etc.; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, and the like; disintegrants such as agar powder, dry starch, alginate, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.

For preparing the dosage unit into suppositories, various carriers well known in the art can be widely used. In the carrier: such as polyethylene glycol, lecithin, cocoa butter, higher alcohols, enzymes of higher alcohols, gelatin, semisynthetic glycerases, etc.

In order to capsule the dosage unit, the active ingredient is mixed with the various carriers described above, and the mixture thus obtained is placed in a hard gelatin capsule or a soft capsule. The active ingredients can also be made into microcapsule, suspension in aqueous medium to form suspension, or hard capsule or injection.

For example, the compositions of the invention are formulated for injection, such as solutions, suspension solutions, emulsions, freeze-dried powder injection solutions, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxy isostearyl alcohol, polyoxyethylene sorbitol lipase, and the like. In addition, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and further, a conventional cosolvent, a buffer, a pH adjuster, and the like may be added. These adjuvants are commonly used in the art.

In addition, colorants, preservatives, flavors, flavoring agents, sweeteners, or other materials may be added to the pharmaceutical formulation as desired.

The dosage of the pharmaceutical composition of the present invention to be administered depends on many factors such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, character and individual response of the patient or animal, the administration route, the number of administrations and the like, and thus the therapeutic dosage of the present invention may vary widely. Generally, the dosages of the compounds of the present invention used are well known to those skilled in the art. The actual effective medicine amount contained in the final preparation in the medicinal composition can be properly regulated to meet the requirement of the effective therapeutic amount, thus completing the treatment of diseases such as obesity, abnormal glucose tolerance, hyperlipidemia, diabetes and complications thereof; and chronic inflammation, insulin resistance, cerebrovascular disease and atherosclerosis.

The antidepressant provided by the invention comprises two stages of prevention and treatment. The dosage of the antidepressant in the prevention stage is as follows: 0.001-3 mg/kg body weight per day; the dosage of the antidepressant in the treatment stage is as follows: each day 0.01-30mg of epilupine (1-epilupine) and its derivatives are provided per kg body weight. The administration mode of the antidepressant is oral administration, nasal spray, instillation or injection; the subject is a mammal, including a human.

The invention provides an antidepressant drug, which takes 0.01-30mg of epilupine (1-EPILUPINE) and derivatives thereof per kilogram of body weight; the antidepressant effect can be produced within 60 minutes after administration. After 5 days of administration, both low and high doses produced significant antidepressant effects. The medicine has the advantages of obvious antidepressant effect, quick response, small dosage, small side effect and the like. In the forced swimming experiment of the mammal mice, the anti-depression effect of epilupine (1-EPILUPININE) and derivatives thereof is more remarkable than that of the conventional antidepressant, namely imipramine.

Compared with the prior art, the invention has the beneficial technical effects that:

1. the invention provides an application of epilupine (1-EPILUPINE) or derivatives thereof in preparing antidepressant drugs. The research result of the invention shows that in the tail suspension experiment of the mammal and the mouse, the epilupine (1-EPILUPINE) or the derivative thereof has the efficacy of rapidly resisting depression and is more effective than the conventional antidepressant, namely imipramine.

2. The invention adopts a forced swimming experiment and a mouse tail suspension experiment as drug screening experiments. The forced swimming experiment and the mouse tail suspension experiment are two commonly used animal behavior despair depression model experiments, and can better ensure the reliability of screening results. The forced swim test in mice has been used for screening of many antidepressants. And most antidepressants with clinical therapeutic effects have been shown to be effective in reducing immobility time in forced swimming experiments.

By immobility is meant that the animal stops struggling in the water, or is in a floating state, only the nostrils are exposed to breathe, and only the small limbs move to keep the head floating on the water. The drug to be screened is administered prior to the assay. Animal behavior is disappointed because the animal is forced to swim so that the animal cannot escape from the harsh environment. The model method is simple, convenient and reliable, and has been widely used for screening and evaluating antidepressant agents. The mouse tail suspension experiment is that the mouse does not struggle under the tail suspension state, and the mouse presents a special quiet immobility state, and the antidepressant can obviously shorten the duration of the immobility state. In the test, the tail of the mice was fixed and suspended upside down. The tail of the mouse is not twisted and folded. And recording the motionless time. The motionless index is: "animal limbs and trunk do not twist and struggle". The tail suspension experiment is sensitive to various antidepressants, and avoids the interference of temperature and animal movement dysfunction in the swimming experiment, so that the result of the forced swimming experiment can be effectively verified and supplemented when some mouse species are used for screening antidepressants.

3. Shows a stronger antidepressant effect than imipramine. In the tail suspension experiment of the mouse animal model, the high-dose group mice (10 mg/kg) of epilupine (1-EPILUPININE) and derivatives thereof begin to relieve symptoms of depression 60 minutes after injection, namely, the activity is more frequent compared with a blank control group, and the immobility time is obviously shortened. Epilupin (1-epilupine) and its derivatives began to significantly shorten tail suspension time after 5 days of injection. Epilupine (1-EPILUPINE) and its derivatives showed stronger antidepressant effect than imipramine at doses (10 mg/kg) lower than imipramine (15 mg/kg).

4. The invention also carries out a mouse Open field experiment (Open field test) to test the autonomous activity of the mouse and avoid the interference of central stimulant. Since the reduction of the immobility time of animals in classical depression animal models is probably caused by the central excitatory action of drugs, the invention also carries out the open-field experiment of mice at the same time. The results show that compared with the control group, the high-concentration epilupine (1-epilupine) and the derivatives thereof have no obvious influence on the autonomous activity of mice, so that the possibility of mania caused by the stimulant can be eliminated, and the epilupine (1-epilupine) and the derivatives thereof have obvious antidepressant effect.

5. The antidepressant drug taking the epilupine (1-EPILUPINE) or the derivative thereof as the active ingredient is hopeful to become a new antidepressant drug with a rapid, efficient and novel mechanism.

Drawings

FIG. 1 shows the structural formula of lupeine (1-EPILUPINE);

FIG. 2 shows lupeine (1-EPILUPINE) ¹ H NMR；

FIG. 3 shows lupeine (1-EPILUPINE) ¹³ C NMR；

FIG. 4 shows MS of lupeine (1-EPILUPINE);

FIG. 5 effect of epilupine (1-EPILUPINE) on mice tail suspension experiment after one hour of injection;

ordinate: tail suspension experimental mice motionless time(s), abscissa: the DMSO control group, the epilupine (1-EPILUPINE) low dose group (ELP-L, 5 mg/kg), the epilupine (1-EPILUPINE) high dose group (ELP-H, 10 mg/kg), the normal saline control group and the imipramine positive control group (15 mg/kg) are sequentially arranged from left to right.

FIG. 6 influence of epilupine (1-EPILUPINE) on swimming experiments in mice 5 days after injection

Ordinate: forced swimming experimental mice immobility time(s), abscissa: the method comprises the following steps in sequence from left to right: DMSO control, epilupine (1-epilupine) low dose group (ELP-L, 5 mg/kg), epilupine (1-epilupine) high dose group (ELP-H, 10 mg/kg), physiological saline control, imipramine positive control (IMI, 15 mg/kg).

Detailed Description

The present invention is described in detail below by way of specific examples, with the understanding that the examples below are merely illustrative and do not limit the scope of the present invention in any way. In the following embodiments, biochemical reagents not specifically described are all conventional in the art, and can be formulated according to conventional methods in the art or commercially available, and are of laboratory purity grade.

Epilupine (1-epilupine), CAS No.: 486-71-5, the laboratory is self-made.

Example 1:

pulverizing semen lupin (Lupinus micranthus) 10 kg, reflux-extracting with 95% ethanol under heating for 3 times (50L each for two hours), concentrating under reduced pressureSuspending 95% ethanol extract in 6L distilled water until the extract reaches 2.5 kg, regulating pH of the water solution to 1-3 with 2mol/L dilute hydrochloric acid solution, extracting with chloroform for 3 times, each time 6L; the aqueous acid solution was then adjusted to pH L0-11 with 2mol/L NaOH solution and extracted 3 times with chloroform 6 liters each. The chloroform was recovered to give 80.0g of total alkaloids. The total alkaloids were coarsely separated by silica gel column chromatography, gradient eluted with chloroform-methanol system (10:0-0:10) to give 6 fractions (Frs. A-F). Wherein Fr.B (9.6 g) is subjected to silica gel column chromatography and Sephadex LH-20 separation and purification to obtain 2g of compound epilupine (1-epilupine). Melting point of 77-78deg.C, dissolving in chloroform, methanol, and ethanol; HR-ESI-MS M/z [ M+H ]] ⁺ 170.1539 it is suggested that its molecular formula is C ₁₀ H ₁₉ NO。

Example 2:

150g of epilupine and a proper amount of auxiliary materials are taken, sieved, mixed evenly and filled into capsules to prepare 1000-grain epilupine capsules. The content of epilupine is obtained according to quantitative analysis and is used as the basis of the dosage.

Example 3:

diluting 150g of epilupine with water, and flavoring with stevioside to obtain 10% liquid preparation, and making into epilupine oral liquid. The content of epilupine is obtained according to quantitative analysis and is used as the basis of the dosage.

Example 4:

taking 100 g of epilupine, dissolving in 500 ml of absolute ethanol, dropwise adding 3% of dilute hydrochloric acid solution until the pH value is=6, standing to separate out epilupine hydrochloride crystals, filtering and drying to obtain epilupine hydrochloride; adding water for injection, fine filtering, bottling, and sterilizing.

Example 5:

taking 200 g of epilupine, dissolving in 1000 ml of absolute ethanol, dropwise adding 5% sulfuric acid ethanol solution until the pH value is=6, standing, precipitating crystals, filtering and drying to obtain epilupine hydrochloride; dissolving in sterile injectable water, adding excipient, stirring to dissolve, filtering with sterile suction filter, sterile fine filtering, packaging in 2 ampoule, lyophilizing at low temperature, sterilizing, and sealing.

Example 6:

adding excipient at a weight ratio of 9:1 to form powder.

Example 7:

the epilupine is added with excipient according to the weight ratio of 1:5-1:10, and the mixture is granulated and tabletted.

Example 8:

taking 50g of epilupine, dissolving in 300 ml of absolute ethanol, dropwise adding 3% phosphoric acid ethanol solution until the pH value is=6, standing, precipitating crystals, filtering and drying to obtain epilupine phosphate; the oral liquid is prepared according to the conventional oral liquid preparation method.

Example 9:

adding excipient at a weight ratio of 5:1, and making into capsule, granule or granule.

Example 10:

adding excipient at a weight ratio of 3:1, and making into capsule, granule or granule.

Example 11:

46.6 g of epilupine, 600 g of starch, 200 g of lactose, 3 g of menthol and 152 g of sodium carboxymethyl starch are added to prepare a lozenge serving as functional food.

Test example 1. Effect of epilupine (1-EPILUPININE) on animal depression model tail suspension experiments

Experimental animals: c57BL/6 mice, male, weighing 30-40 g, supplied by Si Bei Fu (Beijing) Biotechnology Co., ltd., license number: SCXK (Beijing) 2019-0010. Animals are fed in separate cages, the light and shade period is 12h/12h, the room temperature is 20-22 ℃, water is free, and feed is provided by a China large protein experimental animal center. Experimental medicine: epilupine (1-EPILUPINE) was extracted from the pharmaceutical institute of the national academy of medicine, and its chemical purity and structural analysis are shown in FIGS. 1, 2, 3, and 4. Imipramine hydrochloride (Imipramine hydrochloride) is a product of Sigma company, cat No. I7379, lot No. O56K1380. Experimental equipment: a cross bar; an adhesive tape; video camera (Hua is mobile phone); JUNSO multifunction timer. The experimental steps are as follows: male C57BL/6 mice were adaptively bred for one week and divided into 5 groups of 6-8 mice each. The compositions are respectively dimethyl sulfoxide DMSO control group (DMSO dissolved in normal saline), epilupine (1-EPILUPINE) low dose group (ELP-L, 5mg/kg dissolved in DMSO), epilupine (1-EPILUPINE) high dose group (ELP-H, 10mg/kg dissolved in DMSO), conventional antidepressant agent imipramine positive control group (15 mg/kg imipramine dissolved in normal saline) and normal saline control group. The mice are administrated by intraperitoneal injection according to the weight of 0.1ml/10g at 10 am, and 6-8 mice in each group are subjected to tail suspension experiments after 60 minutes of injection; in the tail suspension experiment of the mice, the tail of the mice is stuck on a horizontal cross rod at a position which is 2 cm away from the tail tip by using an adhesive tape, so that the animals are in an inverted hanging state, and the head of the animals is about 15 cm away from a table top. Observe for 6 minutes, record the cumulative immobility time within 4 minutes after. The motionless index is: neither the animal limbs nor the body struggle. The statistical method comprises the following steps: the experimental results are expressed as mean ± SE, and three samples are tested using ANOVA. The average of the two samples (imipramine and saline) was compared with the t-test. The high dose group of epilupine (1-epilupine) mice begin to relieve symptoms of depression 60 minutes after injection, i.e. struggle more frequently than the blank group, and the immobility time is obviously shortened. The activity of the imipramine positive control group is not significantly improved from that of the physiological saline control group within 60 minutes after injection. The results were observed 60 minutes after injection, and the results: c57BL/6 male mice showed significant antidepressant effect in mice tail suspension experiments in the high dose group (10 mg/kg) after 60 min of intraperitoneal injection of different doses of epilupine (1-epilupine) (n=6-10, anova test p < 0.05, p < 0.01). As shown in FIG. 5, the immobility time of the high dose group mice of epilupine (1-EPILUPINE) is reduced from 191.70 + -4.21 s to 164.6+ -6.39 s (P < 0.05) and 160.2+ -6.39 s compared with the DMSO control group, and the result shows that the epilupine (1-EPILUPINE) can be effective in a short time, has remarkable effect, and can resist the depression destimation symptoms caused by forced tail suspension of the mice.

Test example 2. Effect of epilupine (1-EPILUPININE) on forced swimming experiments in animal depression model

Experimental animals: c57BL/6 mice, male, supplied by s Bei Fu (beijing) biotechnology limited, license number: SCXK (Beijing) 2019-0010. Animals are kept in separate cages for one week before the experiment, the light and shade period is 12h/12h, the room temperature is 20-22 ℃, the water is free, and the feed is provided by the China large protein experimental animal center. Experimental drugs: epilupine (1-EPILUPINE) is provided by the national academy of medical science pharmaceutical research. Imipramine is a product of Sigma company, cat No. I7379, lot No. O56K1380. Experimental instrument: glass cylinder (height 40cm, diameter 14 cm); the mouse open box (50 cm long and wide, 40cm high, 16 bottom aliquoting); a thermometer; JUNSO multifunction timer.

The experimental steps are as follows: drug preparation was performed in the same tail suspension experiment. Animal drug injection: c57BL/6 mice, age 7 weeks, weight 30-40 g, adapted to the environment after one week start the experiment. Animals were randomly grouped into 5 groups of 8-10 animals each. Intraperitoneal injection was started every day at 10 am. The injection amount was 0.3 ml/30 g, and the forced swimming experiment was started five days after the injection was performed once per day. Forced swimming experiment: each group of C57BL/6 mice was individually placed vertically in a plexiglas cylinder (40 cm height. Times.14 cm diameter), 25cm water depth, and water temperature 21-23 ℃. Each dosing group and control group were recorded for 6 minutes and the cumulative immobility time of each group of mice was compared over the last 4 minutes. And (3) stationary time judgment: the mice float on the water surface, do no effort to climb out of the cylinder, do only some movements that must keep their heads on the water surface.

The statistical analysis method comprises the following steps: the experimental results are expressed as mean ± SE, and the average of two samples is compared using t-test. Results: c57BL/6 male mice show very remarkable antidepressant effect in forced swimming experiments of the mice after being intraperitoneally injected with different doses of epilupine (1-EPILUPINE) for five days. This antidepressant effect has a stronger trend than the traditional antidepressant drug imipramine (n=8-10 per group of animals, t-test p < 0.05, p < 0.01). As shown in FIG. 6, the immobility time of the mice in both the high-dose group and the low-dose group of epilupine (1-epilupine) was significantly shortened by 4 minutes in forced swimming, compared with the DMSO control group, and the immobility time of the mice in both the low-dose group and the high-dose group of epilupine (1-epilupine) was reduced by 22.50.+ -. 5.20s (p < 0.01) and 23.63.+ -. 4.37s (p < 0.01) from 58.13.+ -. 14.00s, compared with the 1% DMSO control group, respectively, which was shortened by 61.29% and 59.35%. The antidepressant effect of epilupine (1-epilupine) is stronger than that of conventional antidepressant imipramine (24.32% lower).

Test example 3 open field experiment in mice:

since the reduction in immobility time of animals in classical depressive animal models may be due to central excitability effects of drugs, the present invention conducted a mouse open field experiment to examine central excitability of epilupine (1-epilupine). The mice were recorded for 6 minutes after being placed in the middle of the open box. The experimental results show that the total distance of movement of the mice 5 minutes after the open box is (15.64.+ -. 7.50 m) and (15.26.+ -. 3.64 m) compared with the control group (16.62.+ -. 4.32 m) respectively after the high dose and low dose treatments of epilupine (1-epilupine), so that the possibility of causing mania state can be excluded, and thus, epilupine (1-epilupine) does have a significant antidepressant effect.

Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the present invention, which is intended to be covered by the claims of the present invention.

Claims

1. The application of lupin alkaloid or its derivative in preparing medicine for treating depression,

the derivatives of formula (I) include: an organic acid/inorganic acid salt type product of epilupine, and an esterification product or an etherification product of the hydroxyl group at the 11-position.

2. The use of epilupin base or a derivative thereof according to claim 1 for the manufacture of a medicament for the treatment of depression, wherein the medicament further comprises a pharmaceutical ingredient having a positive effect on the treatment of depression.

3. The use of epilupine or a derivative thereof according to claim 2 for the manufacture of a medicament for the treatment of depression, wherein the pharmaceutical ingredients having a positive effect on the treatment of depression comprise: monoamine oxidase inhibitors MAOI, tricyclic antidepressants TCA, selective serotonin reuptake inhibitors SSRI, serotonin and norepinephrine reuptake inhibitors SNRI, noradrenergic and specific 5-HT receptor antagonists NASSA, 5-HT antagonistic and reuptake inhibitors or melatonin and 5-HT2C receptor antagonists.

4. The use of epilupine or a derivative thereof according to claim 2 for the manufacture of a medicament for the treatment of depression, wherein the pharmaceutical ingredient having a positive effect on the treatment of depression is erigeron breviscapus, tiazem, voxepin or bupropion.

5. The use of epilupine or a derivative thereof according to claim 2 for the manufacture of a medicament for the treatment of depression, wherein the pharmaceutical ingredient having a positive effect on the treatment of depression is ketamine.

6. The use of epilupine or derivative thereof according to claim 1, 2, 3 or 5 for the manufacture of a medicament for the treatment of depression, wherein the pharmaceutical dosage form is a powder, granule, tablet, capsule, pill, solution, suspension or injection.