CN101543624B - Purpose of Chilobrachys jingzhao toxin extract-jingzhao toxin-V(JZTX-V) in preparation of drug-breaking medicament - Google Patents
Purpose of Chilobrachys jingzhao toxin extract-jingzhao toxin-V(JZTX-V) in preparation of drug-breaking medicament Download PDFInfo
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Abstract
The present invention relates to the purpose of a polypeptide substance for a medicinal preparation, especially the purpose of Chilobrachys jingzhao toxin extract-jingzhao toxin-V (JZTX-V) prepared by a chemical method in preparation of drug-breaking medicament. The JZTX-V may be used as single effective active component for preparing drug-breaking medicament (opium genus drug). Due to the JZTX-Vmay be combined with tetrodotoxin insensitive sodion channel subtype (Nav 1.8, Nav 1.9) and fugu poison sensitive sodion channel subtype (Nav 1.7) distributed on an external circumstance neuron, it is capable of restraining a correlative voltage gating sodion channel current to stop the conduction of a nerve signal, thereby there is a certain function of breaking opium drug without obvious side effect. The Chilobrachys jingzhao toxin extract-jingzhao toxin-V (JZTX-V) is capable of being used for preparing drug-breaking medicament for treatment of opium genus drug addiction.
Description
Technical field
The present invention relates to the purposes of a kind of polypeptide active substance in medicinal preparation, especially the purposes of Jingzhao chilobrachy spider toxin extract-JZTX-V in the preparation anti-additive medicament.
Background technology
Chinese patent literature CN1872878 (ZL 200610031864.5) discloses the method that from the thick poison of Jingzhao chilobrachy spider extraction separation goes out novel neurotoxin-JZTX-V (below be abbreviated as JZTX-V).JZTX-V is a kind of novel mammalian nervous toxin, and its chemical constitution is the polypeptide of being made up of with specific order 29 amino acid residues, contains three pairs of intrachain disulfide bonds, its chemical constitution as shown in the formula:
Summary of the invention
Purpose of the present invention aims to provide the application of Jingzhao chilobrachy spider toxin extract-JZTX-V in the preparation anti-additive medicament, this toxin can obviously alleviate the withdrawal symptom of morphine addiction mice, in addition, this toxin also has good analgesic effect and does not have toxic and side effects such as similar opioid addiction, and security window is big.
The chemical structural formula of the JZTX-V of indication of the present invention as shown in Figure 1, wherein Y is a tyrosine, C is a cysteine, Q is a glutamic acid, and K is a lysine, and W is a tryptophan, M is a methionine, and T is a threonine, and D is an aspartic acid, S is a serine, and R is an arginine, and A is an alanine, E is a glutamic acid, G is a glycine, and L is a leucine, and I is an isoleucine.JZTX-V can be used as single effective active component and is used to prepare the medicine of giving up opiate addiction.
After opiate addiction is meant that repeated multiple times is used opioid drug, can form psychic dependence and physical dependence, can produce a series of withdrawal symptom group after the acute drug withdrawal, having protracted abstinence symptom (psa) and drug craving in quite a long time behind the inactive medicine, is a kind of chronic recurrent encephalopathy.At present, anti-additive medicament mainly contains several classes, opioid receptor agonist, and as methadone, real is the opioid drug alternative medicine; Non-opioid receptor agonist as clonidine, is alleviated withdrawal symptom; Opiate receptor antagonist as naltrexone, is used for preventing to revert to take drugs after the detoxification; Chinese medicine class drug-breaking medicine.Though but these medicines are given up different therapeutical effect to opiate addiction, itself all has side effect to a certain degree, and drug abstinence is not really desirable.
JZTX-V can combine with Fugu ocellatus toxin non-sensitive type sodium-ion channel hypotype (Nav1.8, Nav1.9) and the Fugu ocellatus toxin responsive type sodium-ion channel hypotype Nav1.7 of distribution of specific on peripheral neurons, suppresses relevant voltage gated sodium ion channel current and the conduction of block nerves signal.JZTX-V has the effect of the withdrawal symptom of obvious suppression morphine addiction mice, and does not have obvious toxic and side effects.This is confirmed by the pharmacology of JZTX-V, effect experiment.
Description of drawings
Fig. 1 is the chemical constitution of ZJTX-V.
Fig. 2 is the influence of JZTX-V to 6 days morphine addiction mouse jump number of times.
Fig. 3 is the influence of JZTX-V to 6 days morphine addiction mice weight loss.
Fig. 4 is that JZTX-V is to shot morphine addiction mouse jump times influence.
Fig. 5 is the influence of JZTX-V to shot morphine addiction mice weight loss.
Fig. 6 is the influence of intracerebroventricular JZTX-V to 6 days morphine addiction mouse jump number of times.
Fig. 7 is the influence of intracerebroventricular JZTX-V to 6 days morphine addiction mice weight loss.
In order better to understand and openly the present invention more fully, test below in conjunction with accompanying drawing and animal pharmacology that the present invention is described in further detail.
The present invention will illustrate the drug treatment function of JZTX-V by two kinds of morphine addiction mouse models and subcutaneous injection and two kinds of routes of administration of intracerebroventricular.Among the figure: * represents to compare with model group significant difference P＜0.05, and * * * represents to compare with model group significant difference P＜0.001.
The specific embodiment
Embodiment 1: subcutaneous injection JZTX-V (its structural formula as shown in Figure 1, down with) is to the therapeutical effect of 6 days morphine addiction mices:
1) primary raw material use in experiment: experiment is to utilize Peptide synthesizer to carry out that the fluorenylmethyloxycarbonyl solid state chemistry synthesizes after reversed-phase HPLC separation and purification and obtaining with JZTX-V, and simultaneously by HPLC and the evaluation of MALDI-TOF mass spectrograph, its purity is more than 98%; Kunming mice is provided by Military Medical Science Institute's Animal House, and between the body weight 18-22g, normal saline and morphine provide by Poison ﹠ Medicine Inst. of Military Medicial Sciences Academy.
2) foundation of 6 days morphine addiction mouse models: continuous 6 days (3 times/day) mouse subcutaneous injection morphines, every day each injection of morphia dosage be followed successively by 10,20,30,40,50,60mg/kg.Injection in the 7th day is (morphine concentration 70mg/kg) once, and 5h pneumoretroperitoneum injection 6mg/kg naloxone is urged withdrawal symptom.Negative control subcutaneous injection every day normal saline (0.2ml/ only), inject time, number of times, naloxone are urged identical with model group.
3) drug dose setting: 50min gave the treatment of subcutaneous injection medicine before Allylnoroxymorphone was urged, and tested medicine JZTX-V dosage is 25 μ g/kg body weight; The dosage of positive control medicine clonidine is 250 μ g/kg body weight, negative control and morphine model group injecting normal saline, and injection capacity is with above testing drug.
4) treatment effectiveness evaluation: number of skips (number of times that mouse jumps in the record 15min behind the injection naloxone 5min); 1h weight loss before and after naloxone is urged.
5) experimental result and analysis
1. number of skips
The number of skips of model group and each administration group is all significantly more than contrast, and has statistical significance (P＜0.001).Compare with model group, clonidine group and JZTX-V (25 μ g/kg) group number of skips significantly reduces (P＜0.05), but indifference (Fig. 2) between clonidine and JZTX-V group.
2. 1h weight loss before and after urging
Before and after urge the 1h weight loss as can be seen, the model group weight loss is apparently higher than contrast, and has statistical significance (P＜0.001), prove that model is successfully.Compare with model group, clonidine group and JZTX-V (25 μ g/kg) group weight loss all significantly reduces (P＜0.05), but indifference (Fig. 3) between clonidine and JZTX-V group.
In a word, the JZTX-V of 25 μ g/kg shows the therapeutic effect suitable with clonidine.
Embodiment 2: subcutaneous injection JZTX-V is to the therapeutical effect of shot morphine addiction mice:
1) experiment use primary raw material: JZTX-V synthetic see test 1; The SD experimental rat is provided by Department Of Medicine, Peking University's animal center, and between the body weight 18-22g, normal saline and morphine provide by Department Of Medicine, Peking University's drug dependence.
2) foundation of 1 injection of morphia mouse model: mouse subcutaneous injection morphine, dosage are 50mg/kg.Contrast injecting normal saline (0.2ml/ only).4.5h pneumoretroperitoneum injection 4mg/kg naloxone is urged withdrawal symptom.
3) drug dose setting: 50min gave the treatment of subcutaneous injection medicine before Allylnoroxymorphone was urged, and tested medicine JZTX-V is provided with four dosage groups, is respectively: 17.5mg/kg, 5.0 μ g/kg, 1.75 μ g/kg and 0.5 μ g/kg body weight; Contrast and morphine model group injecting normal saline, injection capacity is with above testing drug.
4) treatment effectiveness evaluation is with experiment 1.
5) experimental result and analysis:
1. number of skips
The number of skips of model group and each JZTX-V administration group is all significantly more than contrast, and has statistical significance (P＜0.01).Compare with model group, the 5 and 1.75 μ g/kg dosage group number of skips of JZTX-V significantly reduce, and (P＜0.05), but do not have significant difference between two dosage.Other two 17.5 and 0.5 μ g/kg dosage group are lower than model group but difference not significantly (Fig. 4).
2. 1h weight loss before and after urging
From urging back 1h weight loss result to draw, the model group weight loss is apparently higher than contrast, and has statistical significance (P＜0.05), prove that model successfully.Compare with model group, 5, the 1.75 and 0.5 μ g/kg dosage group weight loss of JZTX-V all significantly reduces (P＜0.05), but difference is not remarkable between the three.The difference not significantly (Fig. 5) 17.5 μ g/kg dosage group is lower than model group.
In a word, JZTX-V shows therapeutic effect in low dosage (25 μ g/kg) scope, draws from set 4 concentration experimental results, and 5 and 1.75 μ g/kg, two dosage treatment effects are better, and this result is consistent to the experimental result of 6 days morphine addiction mices with JZTX-V.
Embodiment 3: mice intracerebroventricular JZTX-V is to the therapeutical effect of 6 days morphine addiction mices:
1) experiment tests 2 together with primary raw material.
2) foundation of 6 days morphine addiction mouse models is with experiment 1.
3) drug dose setting: 50min gave right side of mice intracerebroventricular Drug therapy before Allylnoroxymorphone was urged, and tested medicine JZTX-V is 0.5 μ g/kg body weight; Contrast morphine model group injecting normal saline, injection capacity is with above testing drug.
4) treatment effectiveness evaluation is with experiment 1.
5) experimental result and analysis
1. number of skips
The number of skips of model group is all significantly more than contrast, and has statistical significance (P＜0.001), proves that method for establishing model is effective.With the model group ratio, JZTX-V treatment group number of skips significantly reduces (P＜0.001), and with contrast quite (Fig. 6).
2. 1h weight loss before and after urging
From urging back 1h weight loss result to draw, the model group weight loss proves the model success apparently higher than matched group (P＜0.001).Compare with model group, JZTX-V treatment group weight loss significantly reduces (P＜0.001) (Fig. 7).
From testing 2 and 3 results, ventricles of the brain administering effect is about experiment 2 hypodermic 50 times, illustrate that intracerebroventricular treats JZTX-V and directly act on the central nervous system, and the therapeutic effect of its drug rehabilitation is more remarkable.
Claims (1)
1. the application of Jingzhao chilobrachy spider toxin extract-JZTX-V (being abbreviated as JZTX-V) in preparing the medicine that morphine addiction is had the effect of giving up, the chemical structural formula of described JZTX-V is:
Wherein Y is a tyrosine, and C is a cysteine, and Q is a glutamic acid, K is a lysine, and W is a tryptophan, and M is a methionine, T is a threonine, and D is an aspartic acid, and S is a serine, R is an arginine, and A is an alanine, and E is a glutamic acid, G is a glycine, L is a leucine, and I is an isoleucine, it is characterized in that JZTX-V is used to prepare the medicine that morphine addiction is had the effect of giving up as single effective active component.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1485039A (en) * | 2002-09-24 | 2004-03-31 | 王开业 | Antalgic, drug addiction-stopping medication and its preparation method |
| CN100429229C (en) * | 2006-06-22 | 2008-10-29 | 湖南师范大学 | Jingzhao toxin V |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1485039A (en) * | 2002-09-24 | 2004-03-31 | 王开业 | Antalgic, drug addiction-stopping medication and its preparation method |
| CN100429229C (en) * | 2006-06-22 | 2008-10-29 | 湖南师范大学 | Jingzhao toxin V |
Non-Patent Citations (2)
| Title |
|---|
| 曾雄智 等.《敬钊毒素-V的合成、复性及其钾钠通道活性鉴定》.《中国生物化学与分子生物学报》.2008,第24卷(第5期),463－468. * |
| 钱若兵 等.《毒品成瘾的神经机制、治疗现状和进展》.《立体定向和功能性神经外科杂志》.2005,第18卷(第3期),179-182. * |
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