CN116492327A - Application of (2S, 6S) -2, 6-diaminopimelic acid in preparation of anti-postpartum depression drugs - Google Patents
Application of (2S, 6S) -2, 6-diaminopimelic acid in preparation of anti-postpartum depression drugs Download PDFInfo
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- GMKMEZVLHJARHF-WHFBIAKZSA-N LL-2,6-diaminopimelic acid Chemical compound OC(=O)[C@@H](N)CCC[C@H](N)C(O)=O GMKMEZVLHJARHF-WHFBIAKZSA-N 0.000 title claims abstract description 43
- 239000003814 drug Substances 0.000 title claims abstract description 29
- 201000009916 Postpartum depression Diseases 0.000 title claims abstract description 25
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- VBNGJYNPUFWTKX-UHFFFAOYSA-N 10,10-diamino-1,6-dioxacyclotridecane-2,5,7,13-tetrone Chemical compound NC1(CCC(=O)OC(CCC(=O)OC(CC1)=O)=O)N VBNGJYNPUFWTKX-UHFFFAOYSA-N 0.000 description 1
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- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- GLXUWZBUPATPBR-MLWJPKLSSA-N N-Succinyl-L,L-2,6-diaminopimelate Chemical compound OC(=O)C(N)CCC[C@@H](C(O)=O)NC(=O)CCC(O)=O GLXUWZBUPATPBR-MLWJPKLSSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to application of (2S, 6S) -2, 6-diaminopimelic acid in preparing medicaments for preventing and treating postpartum depression. The (2S, 6S) -2, 6-diaminopimelic acid in the application can obviously reduce the depression-like and anxiety-like behaviors of a PPD master mouse, relieve postpartum depression, increase the number of neurons in a CA3 region of a hippocampus of the master mouse, prevent the morphological change and the increase of cell gaps of the neurons, up regulate the relative mRNA expression of a cerebral cortex 5-hydroxytryptamine receptor 2C (Ht 2C), down regulate the relative mRNA expression of hypothalamic adrenocorticotropic hormone releasing hormone (Crh), and has good anti-PPD curative effect.
Description
Technical Field
The invention relates to an organic compound (2S, 6S) -2, 6-diaminopimelic acid, in particular to a novel application of the compound in preparing medicaments for resisting postpartum depression.
Background
Postpartum depression (postpartum depression, PPD) is a marked depression symptom or typical depression onset of women in puerperal period, and clinical characteristics include low emotion, irritability, dysphoria, lack of confidence in life, increased negative emotion and the like (Tang Yahui and the like (2018). A study progress of a postpartum depression animal model and a behavioural evaluation method. Chinese laboratory animal school report. 26 (01): 133-138). The current therapeutic drugs for PPD mainly include selective 5-hydroxytryptamine reuptake inhibitors (SSRI), norepinephrine reuptake inhibitors, estrogens, etc. (rombin et al (2020). Progress in post-natal depression research. Safety and quality control for anesthesia.4 (05): 301-304). Most of the medicines can relieve PPD and reduce recurrence in a short period, but the medicines can cause various side effects, and the phenomena of unconsciousness, slow action, inflexible limb movement and the like of patients can occur. For SSRI drugs which are used very much clinically, only partial patients can be relieved. While in PPD there is a risk of drug delivery to the infant via milk, and early studies have shown that administration during lactation, although only 1-2% enter breast milk, can be potentially harmful to young children, which requires increased vigilance both by the physician and by the mother in selecting medication. And the human body has a blood brain barrier, so that many drugs hardly reach the nerve center through the blood brain barrier.
(2S, 6S) -2, 6-diaminopimelic acid (English name L, L-Diaminopimelic acid) is bacterial and green plant lysine synthesis pathway intermediate products, belonging to the amino acid precursor; lysine synthesis is the final production of L-lysine from L-aspartic acid as the starting material, and the production of N-succinyl-L, L-2, 6-diaminopimelate as the intermediate product by succinyldiaminopimelate disuccinidase. (2S, 6S) -2, 6-diaminopimelic acid is generally a white powder of the formula: c (C) 7 H 14 N 2 O 4 Molecular weight 190.20, boiling point 426.7+ -45.0 ℃, melting point 309-312 ℃, density 1.344+ -0.06 g/cm 3 The acidity coefficient (pKa) is 2.20.+ -. 0.24, readily soluble in water. (2S, 6S) -2, 6-diaminopimelic acid is a completely novel endogenous metabolite, which is only found to possibly inhibit synaptic excitation and amino acid-induced spinal neuronal excitatory reaction, but no report is found on improvement of PPD.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a new application of (2S, 6S) -2, 6-diaminopimelic acid, namely a new application in pharmacy.
The novel application in pharmacy is the application of (2S, 6S) -2, 6-diaminopimelic acid in preparing medicaments for preventing and treating postnatal depression, wherein the chemical structure of the (2S, 6S) -2, 6-diaminopimelic acid is shown as the following formula:
in the above application, the medicament may be a conventional oral preparation such as a tablet, a dripping pill or a capsule.
In the above application, the compound (2S, 6S) -2, 6-diaminopimelic acid may be commercially available (e.g., sigma Aldrich, USA) or may be isolated from human feces or plasma.
In the application, the (2S, 6S) -2, 6-diaminopimelic acid can obviously increase the weight and the sugar preference index of a stressed female mouse, improve the care and anxiety-like behaviors of the female mouse, reduce the hopeless immobility time of the female mouse in a tail suspension experiment, enable the morphology of neurons in a CA3 region of a hippocampus of the stressed female mouse to be recovered normally and increase in quantity, lower the relative mRNA expression of hypothalamic adrenocorticotropic hormone releasing hormone, and regulate the relative mRNA expression of 5-hydroxytryptamine receptor 2C on an epithelial layer, thereby being capable of being used for preparing medicines for preventing and treating postpartum depression (PPD).
Meanwhile, the (2S, 6S) -2, 6-diaminopimelic acid in the application is a key metabolite of key probiotics, and part of the (2S, 6S) -2, 6-diaminopimelic acid is finally metabolized into L-lysine in intestinal tracts to enter blood circulation, so that adverse reactions are small. The pH of milk in lactating women is about 7.09, which is lower than the pH (7.4) in plasma, and acidic drugs are easily ionized in relatively alkaline plasma, and less drug enters the milk, so that compounds with low pKa values, such as (2 s,6 s) -2, 6-diaminopimelic acid, are relatively safe. The (2S, 6S) -2, 6-diaminopimelic acid has simpler structure, small molecular weight (only 190.20) and higher blood-brain barrier passing rate. Based on the characteristics, the medicine for preventing and treating postpartum depression is prepared by taking (2S, 6S) -2, 6-diaminopimelic acid as an active ingredient, so that the risk of the medicine being transmitted to infants through milk can be reduced, and the medicine can easily reach the nerve center through the blood brain barrier.
Drawings
FIG. 1 is a micrograph of Nib stained sections of the CA3 region of the hippocampus of each group of mice.
Detailed Description
The present invention will be further described with reference to specific embodiments and the accompanying drawings, so that those skilled in the art can better understand the technical solutions of the present invention. In the present invention, the materials and equipment used are commercially available or commonly used in the art, unless otherwise specified.
Example 1 (Effect experiment)
1. Establishment of Chronically Unpredictable Mild Stress (CUMS) animals
16 female BALB/c mice (mice) just delivered, with a weight of 30-38 g, are randomly divided into: blank, model, experimental and positive control groups, 4 per group. Except for blank groups, the three groups of groups are subjected to CUMS treatment, and the CUMS treatment method is as follows: from day 2 of the mother mouse delivery, 8: between 00-12:00, one of the short-time stresses is randomly administered; between 15:00-19:00, one of the prolonged stresses is given randomly for up to day 21. Wherein the short-time stress includes: ice water swimming, high stage stress, tail clamping stress, tail suspending stress and oven baking; the long-term stress includes: fasting, water-deprivation, stress limitation, stress in blank, and light irritation. Specific methods of the short-time stress and the long-time stress are as follows: (1) swimming with ice water: putting the mice into a glass barrel with the diameter of 15cm and the barrel height of 40cm, and keeping the water depth of 30cm (4 ℃) for 5min; (2) fasted for 24 hours; (3) water is forbidden for 24 hours; (4) limiting stress: binding the mice with a binder for 2 hours; (5) high stress: the mice were placed on a high table (6 x 160 cm) for 30min; (6) tail clamping stress: clamping tail with vascular artery for 5min at a position 2cm away from tail end of mouse tail; (7) tail-hanging stress: the tail end of the mouse is wound and fixed on a horizontal rod by using an adhesive tape at a position 2cm away from the tail end of the mouse, so that the mouse is kept in a hanging state for 5min; (8) blank stress: no treatment is performed; (9) light stimulation: irradiating with strong light for 12h; and (10) baking in an oven: and baking at 45 ℃ for 5min. Experimental procedure mice were free to eat in addition to stress.
The blank group and the model group are orally infused with sterile physiological saline at a dose of 0.1ml/10g, and the stomach is continuously infused for 20 days from the 2 nd day to the 21 st day, once a day; the experimental group orally administrated (2S, 6S) -2, 6-diaminopimelic acid at a dose of 5mg/kg/d, prepared with sterile physiological saline, and administered once daily by gastric lavage for 20 consecutive days from day 2 of childbirth of the female mice. The positive control group was orally administered fluoxetine hydrochloride at a dose of 2.6mg/kg/d, and was prepared with sterile physiological saline, and the administration was performed once daily for 20 days after the 2 nd day of childbirth of the female mice. After behavioural experiments were performed on days 22-25, the master mice were sacrificed on day 26, brain tissue was harvested, half was stored in a-80 ℃ refrigerator after sagittal incision, and the other half was fixed in paraformaldehyde.
Experimental data results were processed with Excel and significance test was performed using SPSS 21.0 statistical software.
2. Effect of (2S, 6S) -2, 6-diaminopimelic acid (purchased from Sigma Aldrich Co., USA, the same applies below) on CUMS-induced behavior of PPD master mice
The results of the behavioural experiments are shown in the following table, and for the change of the body weight of the female mice (table 1), the model group has a significant difference (p < 0.01) compared with the blank group, the positive control group has a significant difference (p < 0.05) compared with the model group, and the body weight of the stressed female mice on the 26 th day of delivery is significantly higher than the model group (p < 0.01) and slightly higher than the positive control group after the administration of (2S, 6S) -2, 6-diaminopimelic acid, which is similar to the blank group. The experimental result also shows that the administration of (2S, 6S) -2, 6-diaminopimelic acid (experimental group) can obviously increase the weight of the female mice, and the curative effect is slightly better than that of the positive medicine.
In the care behavior of the female mice (Table 2), the model group has a significant difference (p < 0.05) compared with the blank group, the positive control group has a significant difference (p < 0.05) compared with the model group, after the (2S, 6S) -2, 6-diaminopimelic acid is given to the female mice, the incubation period of the female mice in the mouth is significantly shortened (p < 0.05) and is slightly lower than that of the positive control group, which indicates that the intervention of the (2S, 6S) -2, 6-diaminopimelic acid (experimental group) can significantly increase the care behavior of the female mice to the male mice, and the curative effect is slightly better than that of the positive medicine.
In the sugar water preference experiment (table 3), the model group has a significant difference (p < 0.001) compared with the blank group, the positive control group has a significant difference (p < 0.001) compared with the model group, after the (2S, 6S) -2, 6-diaminopimelic acid is given for dry period, the sugar water preference index of the stress female mice is significantly increased (p < 0.05), the pleasure is gradually recovered, but the positive drug curative effect is significantly higher than that of the experimental group (p < 0.01).
In the tail suspension experiment (table 4), the model group had a significant difference (p < 0.0001) from the blank group, the positive control group had a significant difference (p < 0.0001) from the model group, the hopeless immobility time of the stressed female mice was significantly reduced (p < 0.001) after the (2 s,6 s) -2, 6-diaminopimelic acid (experimental group) was administered for the intervention, but the positive drug efficacy was significantly higher than that of the experimental group (p < 0.01).
In open field experiments (table 5), the model group had significant differences (p < 0.001) compared to the blank group, the positive control group had significant differences (p < 0.01) compared to the model group, and after (2 s,6 s) -2, 6-diaminopimelic acid (experimental group) was administered, the time spent in the central zone was longer, the time of activity in the marginal zone was significantly reduced, the total distance of movement was significantly reduced (p < 0.01), indicating that the anxiety-like behavior of the female mice was reduced after (2 s,6 s) -2, 6-diaminopimelic acid (experimental group) administration, but the efficacy was slightly lower than that of the positive drug.
Overall, after administration of (2 s,6 s) -2, 6-diaminopimelic acid by gavage, both depression and anxiety-like behavior of stressed female mice were significantly reduced, with efficacy no inferior to that of the positive drug fluoxetine hydrochloride.
Table 1 day 26 body weights of groups of female mice
Note that: # indicates that p <0.01 compared to the blank group, p <0.05 compared to the model group, p <0.01 compared to the model group, ns indicates no statistical difference compared to the experimental group.
TABLE 2 female mouse loving behavior
Note that: # indicates p <0.05 compared to the blank group, x indicates p <0.05 compared to the model group, ns indicates no statistical difference compared to the experimental group.
TABLE 3 sugar water preference experiment
Note that: # # indicates p <0.001 compared to the blank group, # indicates p <0.05 compared to the model group, # indicates p <0.001 compared to the model group, # indicates p <0.01 compared to the experimental group.
TABLE 4 tail suspension experiment
Note that: # # indicates p <0.0001 compared to the blank group, p <0.001 compared to the model group, p <0.0001 compared to the model group, and p <0.01 compared to the experimental group.
Table 5 open field experiment
Note that: # # indicates p <0.001 compared to the blank, p <0.01 compared to the model, ns indicates no statistical difference compared to the experimental.
2. Effect of (2S, 6S) -2, 6-diaminopimelic acid on morphology and number of neurons in the CA3 region of the hippocampus of CUMS-induced PPD master
After paraffin sections (coronal surfaces) were prepared from the fixed hemispheres, nib staining was performed, and the results are shown in FIG. 1 below. The results show that: normal cells of the blank group of neurons in the CA3 region of the hippocampus, large quantity, compact arrangement and obvious nucleolus; the number of the neurons of the model group is small, the cell body is shrunken, deep dyeing occurs, and the cell gap is increased; the cell structure of the experimental group is obviously recovered to be normal, the number is increased, the cell gap is narrowed, and the staining is uniform; the positive control group had increased cell number and narrowed cell gap. Analysis showed that: the pathological morphology of neurons in CA3 region of the hippocampus of the stressed female mice is obviously improved after the (2S, 6S) -2, 6-diaminopimelic acid is given, and the effect is better than that of a positive medicine.
3. Effect of (2S, 6S) -2, 6-diaminopimelic acid on CUMS-induced hypothalamic Crh, cortical Ht2c in PPD master
Hypothalamus, hippocampus and cortex tissues of each group of mice were subjected to RT-qPCR experiments, and the results are shown in the following table. The results shown in Table 6 demonstrate that: the model group has significant difference (p < 0.05) compared with the blank group, the positive control group has no significant difference compared with the model group, after (2S, 6S) -2, 6-diaminopimelic acid is given to the mice after the dry preparation, the hypothalamus Crh of the stressed mice is significantly down-regulated relative to mRNA expression (p < 0.01), and the curative effect is superior to that of the positive medicine, so that the (2S, 6S) -2, 6-diaminopimelic acid can effectively reduce the reaction of the hypothalamus of the mice to pressure stress. The results shown in Table 7 demonstrate that: the model group had a significant difference (p < 0.01) compared to the blank group, the positive control group had a significant difference (p < 0.05) compared to the model group, after (2S, 6S) -2, 6-diaminopimelic acid was given to the mice after a dry period, the relative mRNA expression of the mouse skin Ht2c was significantly up-regulated (p < 0.05), and the efficacy was slightly better than that of the positive drug, suggesting that (2S, 6S) -2, 6-diaminopimelic acid could improve CUMS-induced changes in relative mRNA expression of PPD mouse skin Ht2c, restoring 5-hydroxytryptamine signaling.
TABLE 6 hypothalamic Crh relative mRNA expression in groups of mice
Note that: # indicates that p <0.05 compared to the blank group, p <0.01 compared to the model group, ns1 indicates no statistical difference compared to the model group, and ns2 indicates no statistical difference compared to the experimental group.
Table 7 relative mRNA expression of the cortex Ht2c of the female mouse in each group
Note that: # indicates p <0.01 compared to the blank group, p <0.05 compared to the model group, ns indicates no statistical difference compared to the experimental group.
Conclusion: the compound (2S, 6S) -2, 6-diaminopimelic acid, which is found by preliminary researches, can remarkably reduce the depression and anxiety-like behaviors of a stressed female mouse; remarkably improving the morphological quantity of neurons in the CA3 region of the hippocampus of the stressed female mouse; significantly down-regulating hypothalamic Crh relative mRNA expression; significantly up-regulates the relative mRNA expression of the epithelial Ht2 c. The effect on female mouse weight, the incubation period of the oral solution, the neuron number morphology, the relative mRNA expression of cerebral cortex Ht2c and hypothalamus Crh is slightly better than that of a positive medicine, and the overall effect of preventing and treating PPD is obvious. Comprehensive analysis shows that the compound is likely to be an endogenous metabolite with potential PPD prevention and treatment effect and can be used for preparing various oral preparations.
Example 2 (Process for the preparation of tablets)
1.9g of (2S, 6S) -2, 6-diaminopimelic acid powder (purchased from Sigma Aldrich Co., USA) and 25-50mg of microcrystalline cellulose are weighed by adopting a wet granulation process, 1.2mg of sodium carboxymethylcellulose is added into 50-100g of lactose monohydrate, the mixture is sieved by a 60-mesh sieve, the mixture is sieved and dispersed again, 6% of hydroxypropyl methylcellulose E5 solution is prepared by mixing, 6% of hydroxypropyl methylcellulose E5 solution is added into the mixture for granulation, the mixture is sieved by a 20-mesh sieve, the mixture is dried for 3 hours at 60 ℃ in an oven, 1.2mg of sodium carboxymethylcellulose, 1.2mg of colloidal silicon dioxide and 1-3mg of magnesium stearate are added into the mixture, and a shallow arc round punching tablet with the diameter of 6.5mm is used for mixing, so that the product is obtained.
Example 3 (preparation method of drop pill)
The prescription for screening is: the mass ratio of the matrix to the PEG4000 to the PEG6000 is 1:1, the material temperature is 85 ℃, the drop distance is 5cm, the cooling temperature is 10 ℃, and the condensate is vegetable oil. 1.9g of (2S, 6S) -2, 6-diaminopimelic acid powder (purchased from Sigma Aldrich Co., USA) is precisely weighed according to the prescription amount, dissolved in a proper amount of purified water, and then a mixture of PEG4000 and PEG6000 is added, and the mixture is placed in a magnetic stirrer water bath kettle with the temperature of more than 80 ℃ and heated and stirred until the mixture is completely melted, and then the two are uniformly mixed. Dripping into dripping pill device with dropper, controlling proper dripping speed, settling in condensate, cooling to form, taking out dripping pill, removing coolant with filter paper, naturally air drying, and selecting pill.
Example 4 (preparation method of Capsule)
1.9g of (2S, 6S) -2, 6-diaminopimelic acid powder (purchased from Sigma Aldrich Co., USA) is weighed, 50-100g of lactose monohydrate and 25-50g of microcrystalline cellulose are added with 1.2mg of sodium carboxymethyl cellulose, the mixture is sieved by a 60-mesh sieve, the mixture is sieved again for dispersion, 6% of hydroxypropyl methylcellulose E5 solution is prepared, 6% of hydroxypropyl methylcellulose E5 solution is added for granulation, the mixture is sieved by a 20-mesh sieve, the mixture is placed in an oven at 60 ℃ for drying for 3 hours, 1.2mg of sodium carboxymethyl cellulose, 1.2mg of colloidal silicon dioxide and 1-3mg of magnesium stearate are added, and the mixture is filled in a hydroxypropyl methylcellulose transparent capsule to obtain the finished product.
Claims (2)
1. Use of (2 s,6 s) -2, 6-diaminopimelic acid for the manufacture of a medicament for the prevention and treatment of postnatal depression, wherein the chemical structure of (2 s,6 s) -2, 6-diaminopimelic acid is represented by the formula:
2. the use according to claim 1, wherein the medicament is in the form of a tablet, drop pill or capsule.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103191141A (en) * | 2012-01-05 | 2013-07-10 | 昆明制药集团股份有限公司 | Application of 3-methoxyl mangiferin in preparing medicine used for treating post-stroke depression |
| WO2023081403A1 (en) * | 2021-11-05 | 2023-05-11 | Terran Biosciences Inc. | Isotopologes, salts, crystalline forms, stereoisomers, of methylone and ethylone and methods of use thereof |
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| CN103191141A (en) * | 2012-01-05 | 2013-07-10 | 昆明制药集团股份有限公司 | Application of 3-methoxyl mangiferin in preparing medicine used for treating post-stroke depression |
| WO2023081403A1 (en) * | 2021-11-05 | 2023-05-11 | Terran Biosciences Inc. | Isotopologes, salts, crystalline forms, stereoisomers, of methylone and ethylone and methods of use thereof |
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