CN1291714C - Application of phenchlobenpyrrone - Google Patents
Application of phenchlobenpyrrone Download PDFInfo
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- CN1291714C CN1291714C CN 200510011028 CN200510011028A CN1291714C CN 1291714 C CN1291714 C CN 1291714C CN 200510011028 CN200510011028 CN 200510011028 CN 200510011028 A CN200510011028 A CN 200510011028A CN 1291714 C CN1291714 C CN 1291714C
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- 239000003814 drug Substances 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 241000699670 Mus sp. Species 0.000 abstract description 21
- 241000700159 Rattus Species 0.000 abstract description 21
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 abstract description 18
- 229960004801 imipramine Drugs 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 9
- 238000010171 animal model Methods 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 239000007928 intraperitoneal injection Substances 0.000 abstract 1
- 230000002787 reinforcement Effects 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000003651 drinking water Substances 0.000 description 9
- 235000020188 drinking water Nutrition 0.000 description 9
- 238000012549 training Methods 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 8
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 230000001430 anti-depressive effect Effects 0.000 description 6
- 230000006399 behavior Effects 0.000 description 6
- 230000003203 everyday effect Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 2
- ZXNRTKGTQJPIJK-UHFFFAOYSA-N aniracetam Chemical compound C1=CC(OC)=CC=C1C(=O)N1C(=O)CCC1 ZXNRTKGTQJPIJK-UHFFFAOYSA-N 0.000 description 2
- 229960000793 aniracetam Drugs 0.000 description 2
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
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- 208000024827 Alzheimer disease Diseases 0.000 description 1
- -1 English name Chemical compound 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 230000008503 anti depressant like effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
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Abstract
The present invention relates to the application of phenchlobenpyrrone, particularly to the application to preparation of medicine for treating depression, which belong to the technical field of medicine application. The present invention adopts two experimental animals of rats and mice and two models of a DRL72-s and an MFST; two medicine application modes of oral taking and intraperitoneal injection are used; difference doses of phenchlobenpyrrone are used, and the present invention has a result that the medicine has obvious anti-depression effect; the effect of the phenchlobenpyrrone is corresponding to that of imipramine, but the toxic and side effect of the phenchlobenpyrrone is less; consequently, the phenchlobenpyrrone can be applied to the preparation of the medicine for treating depression.
Description
Technical field:
The present invention relates to the application of KMBZ-009 Phenchlobenpyrrone., specifically is as the application of preparation treatment depression medicine, belongs to medicinal application
Technical field.
Background technology:
Along with the progress and the development of society, the work rhythm of members of society accelerates, pressure increases, and causes the weak people of part psychological endurance power to suffer from depression.The medicine of now existing treatment depressions, but uncertain therapeutic efficacy is fixed, and also side effect is big, therefore still need continue to seek the little and evident in efficacy new drug of side effect.
The patent No. 94104879.9 discloses the synthetic method and the conduct preparation anti-senile dementia disease thereof of KMBZ-009 Phenchlobenpyrrone. medicine and has strengthened the application of learning and memory medicine.As the inventor of this patent, in the process of implementing this patent, constantly explore and research the new purposes of having opened up the KMBZ-009 Phenchlobenpyrrone. medicine.
List of references:
1, Zhang Juntian. antidepressant pharmacology experimental technique. the modern pharmacology experimental technique. Beijing: Beijing Medical University-combined publication society of China Concord Medical Science University, 1998, P1064, P1068-1069.
2 Nakamura，K.，Aniracetam：its novel therapeutic potential in cerebraldysfunctional disorders based on recent pharmacological discoveries，CNS.Drug Rev.，8(2002)70-89.
3 Nakamura，K.，Tanaka，Y.，Antidepressant-like effects of aniracetam in agedrats and its mode of action，Psychopharmacology(Berl)，158(2001)205-212.
4 Kaufeler，R.，Meier，B.，Brattstrom，A.，Efficacy and tolerability of Ze 117St.John’s wort extract in comparison with placebo，imipramine and fluoxetinefor the treatment of mild to moderate depression according to ICD-10.Anoverview，Pharmacopsychiatry，34 Suppl 1(2001)S49-S50.
Summary of the invention:
The objective of the invention is to open up the new purposes of KMBZ-009 Phenchlobenpyrrone. medicine.
The present invention selects rat and two kinds of laboratory animals of mice for use, 72 seconds low frequency differences formula reinforcement schedulees (DRL72-s) and two kinds of models of forced swimming (MFST), per os gavages or two kinds of administering modes of lumbar injection, use the KMBZ-009 Phenchlobenpyrrone. of various dose, found that this medicine has tangible antidepressant effect, can be used as the application of preparation treatment depression medicine.
The present invention finds that also the antidepressant effect of KMBZ-009 Phenchlobenpyrrone. is with the clinical depression medicine---imipramine is suitable at present, but its side effect is less.
Description of drawings:
Fig. 1 shows: imipramine (n=6) and KMBZ-009 Phenchlobenpyrrone. (n=7) are to the influence (data according to table 1 are drawn) of rat operation DRL72-s reinforcement rate.
Fig. 2 shows: KMBZ-009 Phenchlobenpyrrone. and imipramine are to the influence of mice desperate behavior in the MFST model.The imipramine of 15mg/kg significantly reduce the dead time of mice in water (
*P＜0.05 is compared with the suspending agent matched group).The KMBZ-009 Phenchlobenpyrrone. of 5mg/kg and 10mg/kg obviously shorten the dead time of mice in water (
*P＜0.05,
*P＜0.01 is compared with the suspending agent matched group), each treated animal number average is 10.
The specific embodiment:
1, experiment purpose: the antidepressant effect of observing KMBZ-009 Phenchlobenpyrrone..
2, be subjected to the reagent thing:
Title: Chinese name, KMBZ-009 Phenchlobenpyrrone.; English name, phenchlobenpyrrone; Former name, KMBZ-009.
Content: 99.77%
Lot number: 940090
The unit of providing: Kunming Inst. of Botany, Chinese Academy of Sciences.
Store method: dry sealing is preserved under the room temperature.
Cosolvent: poly-hexylene glycol.Suspending agent: CMC-Na; Now with the current.
3, control drug:
Title: Chinese name, imipramine, English name, imipramine
Cosolvent: normal saline.
4 key instruments:
Behavior control box: U.S. Med Association Inc. company product;
5 animals:
5.1 source, kind, the quality certification number: Kunming Institute of Zoology, Chinese Academy of Sciences's Experimental Animal Center provides Kunming strain mice, and (raise the quality certification number: cloud is defended, moving pipe B05 number.)。Hospital general, Kunming Experimental Animal Center provides the Wistar rat (to raise the quality certification number: No. 9701, the real moving card word in Yunnan.)。
5.2 age, body weight: the mice age was 5 ages in week, and the rat age was 9 ages in week.
5.3 sex: mice male and female half and half; Rat all is male.
5.4 number of animals: mice is 10 for every group, and every group of 5-8 of rat only.
5.5 raising condition: mice and rat from Experimental Animal Center is buied adapted to for 1 week at this laboratory.Illumination in 12 hours, 12 hours unglazed photographs are fully supplied with mouse feed and drinking-water, allow it freely get food and drinking-water.Rat can freely be got food, but control drinking-water.Feedstuff is available from medical biotechnology institute of the Chinese Academy of Medical Sciences.Laboratory is kept quite.
6 experimental designs:
6.1 72 seconds low frequency differences formula reinforcement schedulees (DRL72-s) experiment:
(1) compound method of medicine, dosage setting, route of administration, volume and administration number of times: accurately take by weighing KMBZ-009 Phenchlobenpyrrone., add volume required poly-hexylene glycol and fully dissolve, imipramine disposes with normal saline, uses preparation on the same day same day; The dosage of KMBZ-009 Phenchlobenpyrrone. is 20mg/kg, and the dosage of imipramine is 15mg/kg; Medicine is through lumbar injection (0.2ml/ only), every day single-dose, successive administration 3 days.
(2) near experimental provision: illuminating lamp (making it light yellow in the experiment all the time) and lever are arranged in the behavior control box, drinking device is housed the lever, be in order when requiring, supply water once to it automatically when rat depression bar (reaction).This program requirement, rat only with on reacting space certain hour or make another secondary response more than the certain hour and just can be reinforced (supply water reward) once, otherwise any reaction of rat not only is not reinforced, and interval restarts again.
(3) operating procedure: rat was prohibited water 22.5 hours before undergoing training, and the end back of at every turn undergoing training allows it that freely drinking water the time of 20min arranged.Training step: 1. depression bar operation training: at first trained rat is learned depression bar and is obtained drinking-water in control box.Be that the reaction of animal depression bar once gives the reinforcement of once drinking water, every 60s gave primary reinforcement when reaction did not take place.The rat that every day, 1h learned operation in training yet for three days on end, train separately in addition by the experimenter.2. DRL18-s training: the rat of all association's operation depression bars is accepted the DRL18-s in 2 weeks, and in this training, animal only at depression bar again behind depression bar (reaction) 18s once on the distance, just can obtain the drinking-water award, trains 1h every day.3. DRL72-s training: in this training, animal is depression bar again behind distance depression bar last time (reaction) 18s only, just can obtain the drinking-water award.Train 1h every day.When reaching in the continuous reaction of the depression bar more than the 5d, every rat begins drug test after stable.4. administration test: for three days on end, every day 1 time, 30min carried out the DRL72-s test after the per injection to each group rat lumbar injection imipramine or KMBZ-009 Phenchlobenpyrrone. respectively.The preceding 3 days average achievement of administration is set to baseline values.
(4) observation index: the reinforcement rate, the depression bar number of operations that promptly obtains drinking-water accounts for the percentage rate of control operations number of times.
6.2MFST experiment:
(1) compound method of medicine, dosage setting, route of administration, volume and administration number of times: accurately take by weighing KMBZ-009 Phenchlobenpyrrone., add volume required CMC-Na and make its even suspension, imipramine disposes with normal saline, uses preparation on the same day same day; The dosage of KMBZ-009 Phenchlobenpyrrone. is 2.5,5 and 10mg/kg, and the dosage of imipramine is 15mg/kg; The medicine per os gavages (0.2ml/ only), single-dose.
(2) test set, operational approach and observation index: experimental provision is high 25cm, the glass tank of diameter 15cm.During test, the dark warm water of 18cm (23-25 ℃) of packing in the glass tank, this depth of water must make the tail of mice not touch to be drum head and body support.Per os is given mouse gavaging medicine or suspending agent before the experiment, immediately animal is put into the glass tank of dress water after 60 minutes and observes 6min, and relatively administration group and the control group mice dead time in the 4min of back, promptly mice shows the cumulative time of desperate behavior.What is called is motionless to be that animal does not have other action in water except that keeping one's balance.
7 statistical analysiss: data are expressed as meansigma methods ± standard error, and data are carried out the ANOVA one factor analysis of variance, and p＜0.05 is seen as that there were significant differences.
8 results and evaluation:
8.1DRL72-s test the result: the average reinforcement rate preceding 3 days with administration is foundation level, is set at 1.Reinforcement rate behind every animals administer is compared with basic reinforcement rate and is obtained a relative variation.Found that: behind the lumbar injection positive control drug imipramine (15mg/kg), test result all shows for three days on end, and the reinforcement rate of rat obviously improves; After the lumbar injection 20mg/kg KMBZ-009 Phenchlobenpyrrone., test result showed in first day, and the reinforcement rate of rat increases, but does not reach significant difference, and after second day and the 3rd day lumbar injection KMBZ-009 Phenchlobenpyrrone., the reinforcement rate of rat significantly improves; (the results are shown in Table 1, Fig. 1).This result of study shows that KMBZ-009 Phenchlobenpyrrone. has certain antidepressant effect, and it is active suitable with imipramine.
Table 1: KMBZ-009 Phenchlobenpyrrone. to the influence of rat operation DRL72-s reinforcement rate (
$P＜0.05,
$$P＜0.01 is compared with imipramine group baseline;
*P＜0.05,
*P＜0.01 is compared with KMBZ-009 Phenchlobenpyrrone. group baseline).
| Testing time | Imipramine (15mg/kg) | KMBZ-009 Phenchlobenpyrrone. (20mg/kg) | |
| The reinforcement rate changes | Before the administration for three days on end after (baseline) administration in the 1st day after the administration in the 2nd day after the administration in the 3rd day | 1±0.02 1.21±0.03 $ 1.33±0.02 $$ 1.31±0.02 $ | 1±0.05 1.20±0.09 1.21±0.06 ** 1.51±0.21 * |
8.2MFST experimental result: the dead time of solvent control group mice is more than 100 seconds, show that control group mice shows tangible depressed sample behavior on this model, and after testing preceding 60 minutes singles and gavaging the imipramine of 15mg/kg, the dead time of mice in water obviously shortens than solvent control group mice.After testing the KMBZ-009 Phenchlobenpyrrone. of giving mouse gavaging 5 or 10mg/kg in preceding 60 minutes at forced swimming, the dead time of experiment mice in water obviously reduces than solvent control group mice, and the KMBZ-009 Phenchlobenpyrrone. of 2.5mg/kg dosage does not show appreciable impact to the dead time of mice in water.Show the desperate behavior (the results are shown in Figure 2) that KMBZ-009 Phenchlobenpyrrone. is dose dependent ground and alleviates mice.
More than two groups of experimental results show that KMBZ-009 Phenchlobenpyrrone. has tangible antidepressant effect, the effect of KMBZ-009 Phenchlobenpyrrone. is suitable with the effect of imipramine, but the toxic and side effects of KMBZ-009 Phenchlobenpyrrone. is less, therefore can be used as the application of preparation treatment depression medicine.
Claims (1)
1, the application of KMBZ-009 Phenchlobenpyrrone. is characterized in that the application of KMBZ-009 Phenchlobenpyrrone. as preparation treatment depression medicine.
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| CN1291714C true CN1291714C (en) | 2006-12-27 |
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| CN105495256A (en) * | 2014-10-29 | 2016-04-20 | 范月辉 | Method for processing mung bean flour |
| CN110179784A (en) * | 2019-06-06 | 2019-08-30 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | A kind of application of syringaresinol in the drug of preparation treatment depression |
| CN113683547B (en) * | 2021-09-22 | 2023-03-31 | 中国人民解放军空军军医大学 | Chiral 4,5-disubstituted pyrrolidine-2-ketone compound and preparation method and application thereof |
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Effective date of registration: 20180125 Address after: 100176 building 7511, No. 2, courtyard No. 7, Beijing economic and Technological Development Zone, 7511 Co-patentee after: Kuiming Animal Institute of Chinese Academy of Sciences Patentee after: Beijing Ye He Kang biological medicine technology Co., Ltd. Co-patentee after: Kunming Institute of Botany, Chinese Academy of Sciences Address before: 650223 Institute of animal research, China Academy of Sciences, No. 32 East Road, Yunnan Kunming City, Yunnan Co-patentee before: Kunming Institute of Botany, Chinese Academy of Sciences Patentee before: Kuiming Animal Institute of Chinese Academy of Sciences |