CN104173363A - Application of adenosine compound in preparation of drugs for prevention and treatment of stress disorders - Google Patents
Application of adenosine compound in preparation of drugs for prevention and treatment of stress disorders Download PDFInfo
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- CN104173363A CN104173363A CN201310204455.0A CN201310204455A CN104173363A CN 104173363 A CN104173363 A CN 104173363A CN 201310204455 A CN201310204455 A CN 201310204455A CN 104173363 A CN104173363 A CN 104173363A
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Abstract
The invention discloses application of an adenosine compound WS070133 shown as formula I in preparation of products for prevention or treatment of stress disorders. The stress disorders and related diseases include acute stress disorder, posttraumatic stress disorder, adjustment disorder and phobia, anxiety, mania, bipolar disorder and other diseases. Oral administration of WS070133 on posttraumatic stress disorder model animals shows that the adenosine compound has the effects of lowering animal stress level, reducing fear, anxiety like symptoms and learning and memory impairment. Study also shows that WS070133 can lower the corticosterone level and excitatory amino acid content, reduce apoptosis of neurons and has a regulation effect on related protein molecules. WS070133 has the advantages of low toxicity, no dependence, metabolic and addiction, quick metabolic clearance and no residual effect, etc., thus havaing good application and development prospects. (formula I).
Description
Technical field
The present invention relates to the application of a kind of adenosine compound in stress disorders and relevant disease, particularly WS070133 and physiologically acceptable salt thereof, the purposes in preparation prevention or treatment posttraumatic stress disorder medicine, belongs to medical technical field.
Technical background
Stress disorders and relevant disease comprise acute stress disorder, posttraumatic stress disorder, adjustment disorder and phobia, anxiety neurosis, mania, manic depression.Posttraumatic stress disorder (Posttraumatic Stress disorder, PTSD) claim again retardance psychogenic reaction (delayed psychogenic reaction), to cause a kind of mental disorder disease by Traumatic Events, cause producing the event of PTSD, be a personal story or witness life-threatening event, comprise natural disaster and man power disaster, as earthquake, natural disaster, war, major accident, violent crime etc.Its incidence rate is higher, for family and society bring very big burden.PTSD can be total to the multiple mental diseases such as disease anxiety, depression, substance depilatory, also can be total to the physical diseases such as disease hypertension, bronchial asthma.PTSD patient's suicide risk is far away higher than general population, up to 19%.APA,American Psychiatric Association mental sickness diagnostic & statistical manual (DSM-IV) to the diagnostic criteria of posttraumatic stress disorder is: live through serious traumatic event and have lasting more than 1 month person of following characteristic symptom:
(1) again experience traumatic event, comprise in dreamland, reappear all or part of.
(2) avoid any stimulation relevant with event and occur numb reaction widely, showing as stolidity, emotion paralysis.
(3) emotionality of various ways and physiological arouse and sleep disorder the most common, ability of learning and memory decline.
Drug therapy is one of critical treatment means of PTSD, that main application is maximum in recent years is 5-hydroxy tryptamine reuptake inhibitor (SSRIs), wherein Sertraline (Sertraline, and paroxetine (Paroxetine Zoloft), Paxil) be the unique medicine that is used for the treatment of PTSD by U.S. FDA approval, its side effect comprises drug interaction, gastrointestinal side effect, libido inhibition, suicidal idea and (SSRI) onset is slow, lacks the effect of rapid recovery anxiety.Other drug is if tricyclics (TCA), oxidase inhibitor (MAOI), Benzodiazepines (BZ) are though have certain curative effect, but untoward reaction is more, limit their use, therefore needed to develop the Therapeutic Method of posttraumatic stress disorder safely and effectively.
The chemical formula of WS070133 as shown in Equation 1; chemical name is 5 '-O-capryl-N6-(3-hydroxyl-4-methoxy-benzyl)-adenosine; ((3S; 4R; 5R)-3; 4-dihydroxy-5-(6-((4-hydroxy-3-methoxybenzyl) amino)-9H-purin-9-yl) tetrahy-drofuran-2-yl) methyl decanoate
It is a kind of novel adenosine derivant of synthesizing as lead optimization structure taking the active components A MG-1 of traditional medicinal plants Armillaria mellea, inventor's early-stage Study shows that WS070133 can reduce the anxiety sample symptom of animal, the sleep of induction physiological, and without addiction, internal metabolism is all very fast with removing, has wider safe dose scope.
By the end of so far, have no WS070133 and analog structure compound for preventing and treating the relevant report of posttraumatic stress disorder and relevant disease.
Summary of the invention
The technical problem to be solved in the present invention is, the product of a kind of new prevention, alleviation and/or treatment stress disorders and relevant disease is provided, be the compound shown in formula 1 and/or its at physiologically acceptable salt, prevention, alleviate and/or treatment stress disorders and relevant disease preparing product in application.
Described stress disorders and relevant disease are selected from acute stress disorder, posttraumatic stress disorder, adjustment disorder and phobia, anxiety neurosis, mania, manic depression.Described product comprises medicine, food, health product.
The present invention tests first the oral pharmacodynamic evaluation through stomach administration prevention and treatment PTSD of WS070133 on animal model, finds that WS070133 can significantly reduce the PTSD sample symptom of PTSD animal pattern.
The present invention realizes by following technical solution: conditionality electric shock (Conditional foot shock) animal test model and the PTSD multiple stress animal model (Combined stress model) of application simulation PTSD, within continuous 2 weeks, orally give WS070133 through stomach at animals received stress stimulation from starting, and after two weeks, carry out corresponding Animal Behavior Science and detect and the Related Drug pharmacological research of WS070133 to PTSD preventive and therapeutic effect.
The method that in the present invention, WS070133 can provide by patent application " a kind of adenosine derivative and its preparation method and application " (application number 200910081639) prepares.
Useful technique effect:
WS070133 can be used for prevention, alleviate and/or the disease such as treatment stress disorders relevant disease and phobia, anxiety neurosis, mania, manic depression, makes up the deficiency of traditional downern Benzodiazepines and opiates.
Brief description of the drawings
Fig. 1-1.PTSD conditionality electric shock model flow chart.
Fig. 1-2 .WS070133 is on the stiff firmly impact of behavior of PTSD conditionality electric shock model mice.
n=10。
The impact of Fig. 1-3.WS070133 on PTSD conditionality electric shock model mice exploratory behavior.
n=10。
The impact of Fig. 1-4.WS070133 on the labyrinth behavior of the overhead cross of PTSD conditionality electric shock model mice.
n=10。
Fig. 2-1.PTSD combined stress model flow chart
The impact of Fig. 2-2.WS070133 on PTSD combined stress model mice background fear (A) and clue sex dread (B).
n=12。
The impact of Fig. 2-3.WS070133 on PTSD combined stress model mice elevated plus-maze test.
n=12。
The impact of Fig. 2-4.WS070133 on PTSD combined stress model mice open field test.
n=12。
The impact of Fig. 2-5.WS070133 on PTSD combined stress model mice Novel object identification experiment.
n=12。
The impact of Fig. 2-6.WS070133 on PTSD combined stress model mice Morris water maze laboratory.(A) water maze orientation navigation test, (B) water maze space exploration test.
n=12。
Fig. 3. Flow cytometry Hippocampus apoptosis result.
n=7。
Fig. 4. different group hippocampal dentate TUNEL coloration results.
n=3。
Fig. 5 .ELISA measures plasma corticosterone content.
n=6。
Fig. 6. quantitative PCR is measured Hippocampus sugar/mineralcorticoid receptor and is expressed.
n=3。
Fig. 7. the expression of each treated animal Hippocampus pro apoptotic protein Bax and anti-apoptotic proteins Bcl-2,
(A) immunoblotting detects protein expression, n=7.(B) quantitative PCR detection rna expression, n=3.
Detailed description of the invention
The invention discloses the purposes of WS070133 in preparation prevention or treatment posttraumatic stress disorder medicine, those skilled in the art can use for reference content herein, realize this invention by suitable improvement technological parameter.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, within they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can change methods and applications as herein described in content of the present invention, spirit and scope or suitably change and combination not departing from, and realizes and apply the technology of the present invention.
In order to make those skilled in the art understand better technical scheme of the present invention, below in conjunction with specific embodiment, the present invention is described in further detail.
The effect of embodiment 1:WS070133 in PTSD mice conditionality electric shock model
One, main method
1. experimental provision:
The overhead cross of mice labyrinth (institute of Materia Medica,Chinese Academy of Medical Sciences development).
Mice prologue device (Shanghai Yishu Information Technology Co., Ltd.).
YLS-9A physiological and pharmacological electronic stimulation instrument (Jinan, Shandong Province Yi Yan development in science and technology company limited)
Mice electric shock case (institute of Materia Medica,Chinese Academy of Medical Sciences development)
Mice diving tower case/keep away camera bellows (institute of Materia Medica,Chinese Academy of Medical Sciences development)
2. laboratory animal:
60 of SPF level ICR healthy male mices, are provided by Beijing Vital River Experimental Animals Technology Co., Ltd., animal quality certification SCXK (capital) 2009-0007.Initial body weight 12-14g, 10 every group.22 ± 2 ° of C of room temperature, temperature 40-50%, well-ventilated, is placed under circadian rhythm illumination condition, and ad lib water inlet, raises 5 days to conform.
3. model preparation:
In Day0 and Day1, mice is put into electric shock case, adapt to after 2 minutes, carry out intermittent vola electricity irritation in 5 minutes (intensity 1mA continues 10 seconds, 10 seconds, interval), continuous 2 days.In Day2, Day7 and Day14, mice is put into electric shock case again, be exposed in electric shock environment 5 minutes, but do not accept electric shock.Blank group is pressed identical step process, but does not accept electric shock, and experiment flow is shown in Fig. 1-1.
4. tested medicine:
WS070133 is provided by institute of Materia Medica,Chinese Academy of Medical Sciences, molecular weight 557, purity >90%; Positive drug: paroxetine, Sino-America Tianjin Shike Pharmaceutical Co., Ltd. produces, lot number: 11030748; Solubilizing agent: hydroxypropyl cyclodextrin (HP-β-CD, analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group); 20%HP-β for WS070133 and paroxetine-CD dissolves, and is made into respective concentration.
5. animal grouping and administration:
60 of ICR male mices, are divided into 6 groups at random, 10 every group, be respectively Normal group, model group, positive controls, WS070133-7.5mg/kg, WS070133-15mg/kg and WS070133-30mg/kg, from stress successive administration a few days ago 2 weeks.After two weeks, observe behavioristics's performance and the Biochemical Indexes of animal.
Two, main result
1. compared with Normal group, model group animal shows obvious deadlock and lives behavior in electric shock environment, and WS070133 administration group (15,30mg/kg) has reduced the deadlock of animal and lived behavior, demonstrates the inhibitory action to fear reaction, and experimental result is shown in Fig. 1-2.
2. refusing to capture in reaction evaluating, model group animal demonstrates the feature of great vigilance, and it is refused prisoner's scoring and is significantly higher than Normal group, and the prisoner's scoring of refusing of WS070133 administration group is compared model group and significantly reduced, and the results are shown in Table 1; Exploratory behavior measurement result display model treated animal has anxiety level and raises, and compared with model group, WS070133 administration group anxiety level reduces, and the results are shown in Figure 1-3.
Table 1.WS070133 refuses to capture reactive impact to PTSD conditionality electric shock model.
Refuse prisoner reaction scoring: with animal never contacted glove grab mice, observe its reaction.Scoring criteria: be easy to capture 0 point of animal note; Scream or avoid 1 point of note; Scream and avoid 2 points of notes; Escape 3 points of notes; Escape and scream and remember 4 points; Attempt to bait 5 points of glove notes; Initiatively jump up and attack 6 points of notes.
n=10。
3. dark experimental result display model group ability of learning and memory reduction is tested and kept away to diving tower, and WS070133 has certain improvement effect to the ability of learning and memory decline of stressed animal, the results are shown in Table 2.
The impact of table 2.WS070133 on PTSD conditionality electric shock animal pattern ability of learning and memory (diving tower and keep away dark experiment).
n=10。
4. WS070133 can reduce the content of central excitation acidic amino acid mediator (glutamic acid) afterwards, and then weakened the glutamate receptor function strengthening that excessively adverse effect of enhancing in PTSD remembered as mediated Excitotoxicity and Traumatic Events, the results are shown in Table 3.
The amino acid neurotransmitters assay of table 3. cerebral cortex and Hippocampus
(the μ mol/g of unit,
n=5)
The effect of embodiment 2:WS070133 in PTSD mice combined stress model
One, main method
1. experimental provision:
The overhead cross of mice labyrinth (institute of Materia Medica,Chinese Academy of Medical Sciences development).
Mice prologue device (Shanghai Yishu Information Technology Co., Ltd.).
YLS-9A physiological and pharmacological electronic stimulation instrument (Jinan, Shandong Province Yi Yan development in science and technology company limited)
Mice electric shock case (institute of Materia Medica,Chinese Academy of Medical Sciences development).
Mice water maze (institute of Materia Medica,Chinese Academy of Medical Sciences development)
Mice stationary magazine creel (Jinan, Shandong Province Yi Yan development in science and technology company limited)
2. laboratory animal:
72 of clean level Male Kunming strain mice, Beijing HFK Bio-Technology Co., Ltd. provides, credit number: SCXK (capital) 2009-0007.Initial body weight 12-14g, 12 every group.Raise in 22 ± 2 ° of C of room temperature, relative humidity 40-50%, in aeration-drying, quiet environment, circadian rhythm illumination in 12 hours, freely ingests, drinks water, and raises 5 days to conform.
3. model preparation:
From Day1 to Day5, carry out conditionality foot electric shock (Conditioned foot shock, CF), mice is put into electric shock case, adapt to, after 1 minute, open sodium yellow photograph, (intensity 1mA shocked by electricity after 10 seconds, continue 5 seconds), the rear stop 20 seconds of having shocked by electricity, puts back to former cage subsequently.Day6 carry out single continuously stress (Single prolonged stress, SPS), first animal was confined after 2 hours, forced swimming 20 minutes, recover after 15 minutes, etherization, to loss of consciousness, moves to ventilation and makes it naturally recover, normal raising after one week carried out corresponding behavioristics and mechanism experiment, and model preparation flow is shown in Fig. 2-1.
4. tested medicine:
WS070133, white powder, water insoluble, institute of Materia Medica,Chinese Academy of Medical Sciences provides, molecular weight 557, purity >90%; Positive drug: paroxetine, Sino-America Tianjin Shike Pharmaceutical Co., Ltd. produces, lot number: 11030748; Solubilizing agent: hydroxypropyl cyclodextrin (HP-β-CD, analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group); 20%HP-β for WS070133 and paroxetine-CD dissolves, and is made into respective concentration.
5. animal grouping and administration:
72 of Male Kunming strain mice, are divided into 6 groups at random, 12 every group, be respectively Normal group, model group, positive controls, WS070133-7.5mg/kg, WS070133-15mg/kg and WS070133-30mg/kg, from stress successive administration a few days ago 2 weeks.After two weeks, observe behavioristics's performance and the Biochemical Indexes of animal.
Two, main result
1. compared with Normal group, after model group Animal stress one week, electric shock environment and electric shock clue (sodium yellow shines) are showed to obvious frightened behavior, show as stiff firmly time increase, paroxetine and WS070133 (15,30mg/kg) alleviated to some extent the frightened behavior of animal, experimental result is shown in Fig. 2-2.
2. overhead cross labyrinth and open field test show that stressed animal obviously rises in strange environment anxiety degree of lower time, and WS070133 administration treated animal anxiety level is compared model group and significantly reduced, and the results are shown in Figure 2-3 and Fig. 2-4.
3. Novel object identification is compared normal group with the learning and memory of water maze laboratory display model treated animal obvious decline, and WS070133 declines and shows protective effect to a certain degree the learning and memory of stressed animal, and experimental result is shown in Fig. 2-5 and Fig. 2-6.
4. flow cytometer showed and immunohistochemical staining result show that WS070133 also can reduce the apoptosis of hippocampal neurons afterwards, and experimental result is shown in Fig. 3 and Fig. 4.
5. WS070133 has the effect that irritability level of adrenocortical hormone raises that suppresses, thereby the cranial nerve cell that protection causes because level of adrenocortical hormone raises damage and synaptic function damage, and experimental result is shown in Fig. 5.
6. WS070133 has regulating action to the expression of Hippocampus sugar/mineralcorticoid receptor afterwards, by reducing the overexpression of glucocorticoid receptor (GR), raises the expression performance protective effect of mineralcorticoid receptor, and experimental result is shown in Fig. 6.
7. immunoblotting and quantitative PCR result show that WS070133 has reduced the expression of short apoptosis molecule Bax, have raised the expression of anti-apoptosis molecule Bcl-2, and experimental result is shown in Fig. 7.
In sum, WS070133 has the effect that reduces PTSD animal pattern fear, anxiety, learning memory injury, and can reduce the Corticosterone Level increase that strongly stress cause, and reduces Neuron Apoptosis, regulates the features such as sugar/mineralcorticoid receptor level.WS070133 can be used for prevention, alleviates and/or treats stress disorders relevant disease as diseases such as acute stress disorder, posttraumatic stress disorder, adjustment disorder and phobia, anxiety neurosis, mania, manic depression.
Claims (4)
1. adenosine compound and the application in preparation prevention, alleviation and/or treatment stress disorders and relevant disease product at physiologically acceptable salt thereof as shown in Equation 1.
2. according to the application of claim 1, it is characterized in that, described stress disorders is selected from acute stress disorder, posttraumatic stress disorder, adjustment disorder.
3. according to the application of claim 1, it is characterized in that, the relevant disease of described stress disorders is selected from phobia, anxiety neurosis, mania, manic depression.
4. according to arbitrary described application in claim 1-2, it is characterized in that, described product comprises medicine, food, health product.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112220782A (en) * | 2020-11-11 | 2021-01-15 | 中国人民解放军军事科学院军事医学研究院 | Application of 1,2, 4-trimethoxy benzene in preventing and treating posttraumatic stress disorder |
| CN113648320A (en) * | 2021-08-16 | 2021-11-16 | 中国人民解放军军事科学院军事医学研究院 | Medical application of siloxibin in resisting post-traumatic stress disorder |
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| CN101857622A (en) * | 2009-04-07 | 2010-10-13 | 中国医学科学院药物研究所 | Adenosine derivative, and preparation method and application thereof |
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| CN101602786A (en) * | 2008-06-10 | 2009-12-16 | 中国医学科学院药物研究所 | N 6-substituted adenosines derivative, its method for making and pharmaceutical composition and purposes |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112220782A (en) * | 2020-11-11 | 2021-01-15 | 中国人民解放军军事科学院军事医学研究院 | Application of 1,2, 4-trimethoxy benzene in preventing and treating posttraumatic stress disorder |
| CN112220782B (en) * | 2020-11-11 | 2021-08-20 | 中国人民解放军军事科学院军事医学研究院 | Application of 1,2, 4-trimethoxy benzene in preventing and treating posttraumatic stress disorder |
| CN113648320A (en) * | 2021-08-16 | 2021-11-16 | 中国人民解放军军事科学院军事医学研究院 | Medical application of siloxibin in resisting post-traumatic stress disorder |
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