CN101632653A - BAPTA and application of derivant thereof in preparing analgesic drugs - Google Patents
BAPTA and application of derivant thereof in preparing analgesic drugs Download PDFInfo
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- CN101632653A CN101632653A CN200910144754A CN200910144754A CN101632653A CN 101632653 A CN101632653 A CN 101632653A CN 200910144754 A CN200910144754 A CN 200910144754A CN 200910144754 A CN200910144754 A CN 200910144754A CN 101632653 A CN101632653 A CN 101632653A
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- bapta
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Abstract
The invention discloses a BAPTA and an application of a derivant thereof, in particular to an application of the derivant in preparing analgesic drugs. Clinical indications include headache, prosopalgia, dysmenorrheal, postoperative pain, cancer pain, viscera pain, postherpetic neuralgia, phantom limb pain, HIV, pathologic pain related to multiple sclerosis, morphine class medicine tolerance or addiction patient pain and serious chronic intractable pain or usual clinical pain diseases.
Description
Technical field
The present invention relates to the purposes of a compounds and derivant thereof, specifically is the purposes of BAPTA and derivant thereof.
Background technology
Pain is very common clinically symptom, and it can make the patient produce offending emotions such as anxiety, anxiety, uneasiness, fear, and serious pain can cause shock.Can ease the pain sensation and change emotional response of analgesic to pain.Analgesic generally can be divided into opiates and non-opium. and opium kind analgesics can be used for serious pain or moderate pain, representing medicine is morphine, but this type of medical instrument has the dependency that causes in various degree, use the back patient to produce physical dependence and psychic dependence repeatedly, necessary strict grasp indication and restriction use to it; The classical medicine of nonopioid analgesic is an aspirin, is mainly used in the patient of mild pain, for severe pain or intractable pain weak effect, it is generally acknowledged that their nothings rely on potentiality.
Overcoming the defective of opiates and nonopioid analgesic commonly used, be the clinical new type analgesic that high-efficiency low-toxicity is provided, is the long-term pursuit of medical scientific research.
Summary of the invention
The invention provides BAPTA and derivant thereof the purposes aspect the preparation analgesic, the BAPTA derivant can reduce the endocellular liberation calcium concentration, alleviates or eliminate the effect of calcium overload, improves the pain threshold values, reduce the sensitivity of human body, play the analgesic effect thermostimulation or chemical stimulation.
The application aspect the preparation analgesic of BAPTA of the present invention and derivant thereof; Described BAPTA derivant is meant that BAPTA esterification products or phenyl ring have substituent esterification products, and chemical formula is:
X in the formula
1-X
4Be identical group, or different groups; Expression C
nH
2n+1, n=2-8, or C
nH
2n+1(OCH
2CH
2)
m, n=1-18, m=1-3;
A and B represent the substituent group on the phenyl ring, are H, CHO, COOH, NO
2, NHR, CF
3, alkyl, halogen or alkoxyl,
Two phenyl ring are symmetric, or asymmetric.
Described BAPTA pair-adjacent phenalgin oxirane group-N, N ,-N ', N '-tetraacethyl are a kind of calcium chelating agent, combine with calcium ion, reduce free calcium ion concentration.
The purposes of described BAPTA and derivant thereof is characterized in that: the chemical formula of described BAPTA derivant is:
Wherein: X represents C
nH
2n+1, n=2-8, or C
nH
2n+1(OCH
2CH
2)
m, n=1-18, m=1-3;
A, B represents H, CHO, COOH, NO
2, NHR, CF
3, alkyl, halogen or alkoxyl;
Two phenyl ring are symmetric, or asymmetric.
The purposes of described BAPTA and derivant thereof is characterized in that: the chemical formula of described BAPTA derivant is:
Wherein: X represents C
nH
2n+1, n=2-8, or C
nH
2n+1(OCH
2CH
2)
m, n=1-18, m=1-3;
E represents disodium or calcium;
A, B represents H, CHO, COOH, NO
2, NHR, CF
3, alkyl, halogen or alkoxyl,
Two phenyl ring are symmetric, or asymmetric.
The mechanism of action of described BAPTA derivant is that calcium ion is the coupling connection factor that presynaptic membrane is excited and mediator release is necessary, noxious stimulation causes that the release of neurotransmitter is relevant with the activity of calcium electric conductance with the voltage-dependent on the synapse telolemma, the BAPTA derivant can reduce the endocellular liberation calcium concentration, alleviate or eliminate the effect of calcium overload, improve the pain threshold values, reduce the sensitivity of human body, play the analgesic effect thermostimulation or chemical stimulation.
The clinical indication of described analgesic includes: headache, trigeminal neuralgia, dysmenorrhea, postoperative pain, cancer pain, visceral pain, post-herpetic neuralgia, phantom pain, HIV, pathological pain, the tolerance of morphine class medicine or addiction patient's the pain that multiple sclerosis is relevant, serious chronic intractable pain or clinical common pain disease.
Described BAPTA and derivant thereof are used to prepare analgesic, can be made into tablet, pill, capsule, injection or other suitable dosage forms.
BAPTA of the present invention and derivant thereof are used and the preparation analgesic, and described analgesic has rapid, the rapid-action advantage of effect.
BAPTA derivant effect characteristics are: to the high selectivity of calcium, and to the very low (Ca of selectivity of magnesium
++: Mg
++=105) to protect cell to reducing calcium overload be favourable to this point, because Mg
++Be Ca
++The physiological antagonism agent; Be subjected to the pH variable effect very little; With calcium generation effect fast (doubly) than ethylene glycol-two-fast 50-400 of (2-amino-ethyl) tetraacethyl EGTA; With the calcium complexation fluorescence not taking place, can not produce possible light toxic action.
The BAPTA derivant is compared with the N type calcium channel effect on the analgesics ziconotide block nerves cell membrane, the BAPTA derivant can directly reduce intracellular calcium concentration, with regard to the regulation and control of calcium ion concentration in the neurocyte, BAPTA derivant and analgesics ziconotide exercising result basically identical illustrate that the BAPTA derivant has the similar analgesic activity of ziconotide.
The specific embodiment
The reaction of BAPTA and acetyl-o-methyl generates acetyl oxygen methoxyl group four nitriles (BAPTA-AM), and BAPTA-AM has very high fat-soluble, and permeate through cell membranes plays a role in cell, so be called " cell permeability " again.BAPTA-AM is processed into liposome with suitable adjuvant, solves the key issue on the pharmaceutics, makes the BAPTA-AM can intravenous administration, and effect rapidly, and is rapid-action.HXB-08 is the water solublity disodium salt of BAPTA, and molecular formula is C
42H
62N
2O
12Na
2
The present invention utilizes the BAPTA derivant to reduce the endocellular liberation calcium concentration directly, rapidly, alleviate or eliminate the effect of calcium overload, adopt mice formalin model, mice hot water whipping model, mouse writhing model to the BAPTA derivant, BAPTA-AM, the BAPTA-AM liposome, HXB-08 has carried out the comparatively research of the analgesic activity of system, understands its analgesic activity intensity, estimates its timeliness and dose-effect relationship.
The research of BAPTA derivant analgesic activity:
1, mice hot water whipping experiment:
The light holding of left hand is decided mice, exposes the Mus tail, and about 3cm (bath temperature remains on 50 ± 0.5 ℃), record TCL (tail-curl latency inserts in the water to the time that retraction reacts takes place from the Mus tail) is for surveying pain index evaluation drug effect in the immersion hot water.Administration space before 5min surveys TCL value twice, gets its meansigma methods as the basic threshold of pain.Measure the TCL value of 15min, 30min, 60min, 120min after the administration.
The result: each organizes the no statistics difference of TCL value, each dosage group of BAPTA liposome and morphine group after administration all significant prolongation mice TCL value.Onset in the BAPTA liposome 15min, 120min is kept in effect.
HXB-08 8mg/kg does not have obviously to improve the hot water whipping threshold value of mice, and HXB-08 12mg/kg, 16mg/kg, 20mg/kg have significantly improved the TCL value of mice.
2, mice formalin method (formalin test):
Behind the administration 30min with 10 μ L microsyringes only to the formalin 10 μ L/ of the right back sufficient sole subcutaneous injection 5% of mice, immediately mice is put into a 2000ml glass beaker that hangs, minute surface observed and recorded mice by 30cm place under the beaker licked by the time of injection foot, and licking the foot time with the accumulation of injecting back 0～5 minute is reaction evaluating medicine analgesic effect.
The result: each dosage group of BAPTA liposome and morphine group have all significantly reduced the sufficient time of licking of mice (P＜0.001) after administration.
12mg/kg HXB-08 can significantly reduce the sufficient time of licking of mice (P＜0.01), but 4mg/kg and 8mg/kg dosage group do not make significant difference to the mice threshold of pain.
3, mouse writhing method (writhing test):
Administration 30min injects 0.6% glacial acetic acid (0.2ml/ only) in the mouse peritoneal, stimulate visceral layer and parietal peritoneum, cause that the deep is than the long inflammatory pain of large tracts of land, causing mice abdominal part indent, trunk and hind leg to occur upholds, behavior reactions such as hips up are called writhing response (writhing response).This is reflected at frequency of occurrences height in the 15min of injection back, so be the pain quantitative target to inject the body number of times of turning round that takes place in the back 15min.
BAPTA liposome 2mg/kg is no obvious analgesic activity in the mouse writhing model, and 4mg/kg (P＜0.01) and 6mg/kg (P＜0.001) have all significantly reduced mice causes turning round body because of chemical stimulation number of times.
4, BAPTA-AM derivant intracerebroventricular injection analgesic activity:
With hands a mice abdomen position is fixed during administration, connect syringe needle No. 4 with the 0.25ml syringe, between mouse head two tramlines and two lines, about higher slightly median line and sagittal suture intersection point on the skull position at each 2mm place, entry needle is vertically thrust, the degree of depth is 2mm (fixing at needle point with plastic bushing in advance), and injection shot is no more than 10 μ L, about inject time 10s.
Experiment mice is divided into normal saline group, solvent control group (DMSO), morphine group (0.06mg/kg), BAPTA-AM 0.05mg/kg, 0.1mg/kg, 0.2mg/kg group, intracerebroventricular injection administration at random.
Solvent DMSO does not have obviously influence to the TCL value of mice, and BAPTA-AM can significant prolongation mice TCL value through the tricorn administration.
Solvent DMSO does not have obvious influence to the threshold of pain of mice, and BAPTA-AM can significantly reduce mice through the tricorn administration and lick the sufficient time (P＜0.001).
Solvent DMSO does not have obvious influence to the threshold of pain of mice, and BAPTA-AM can significantly suppress mice pain due to the chemical stimulation through the tricorn administration, and effect has dose dependent.
5, sum up:
BAPTA derivant BAPTA-AM, BAPTA liposome, HXB-08 all can improve the pain threshold of mice in the experiment of pain model, reduce the sensitivity of mice to thermostimulation or chemical stimulation, have significant analgesia role, the experiment of intracerebroventricular injection administration shows that the central nervous system is that the BAPTA derivant produces one of analgesic site of action.BAPTA liposome, BAPTA-AM and HXB-08 under the test dose do not produce obvious toxic and side effects to mice, safety is higher, therefore, the BAPTA derivant has the potentiality as analgesic, and the exploitation of its analgesic activity is had high theoretical and practical significance.
Claims (7)
1, the purposes of BAPTA and derivant thereof is characterized in that: the application aspect the preparation analgesic of described BAPTA and derivant thereof;
The BAPTA derivant is meant that BAPTA esterification products or phenyl ring have substituent esterification products, and chemical formula is:
X in the formula
1-X
4Be identical group, or different groups; Expression C
nH
2n+1, n=2-8, or C
nH
2n+1(OCH
2CH
2)
m, n=1-18, mm=1-3;
A and B represent the substituent group on the phenyl ring, are H, CHO, COOH, NO
2, NHR, CF
3, alkyl, halogen or alkoxyl,
Two phenyl ring are symmetric, or asymmetric.
2, the purposes of BAPTA according to claim 1 and derivant thereof is characterized in that: described BAPTA pair-adjacent phenalgin oxirane group-N, and N ,-N ', N '-tetraacethyl are a kind of calcium chelating agent, combine with calcium ion, reduce free calcium ion concentration.
3, the purposes of BAPTA according to claim 1 and derivant thereof is characterized in that: the chemical formula of described BAPTA derivant is:
Wherein: X represents C
nH
2n+1, n=2-8, or C
nH
2n+1(OCH
2CH
2)
m, n=1-18, m=1-3; A, B represents H, CHO, COOH, NO
2, NHR, CF
3, alkyl, halogen or alkoxyl; Two phenyl ring are symmetric, or asymmetric.
4, the purposes of BAPTA according to claim 1 and derivant thereof is characterized in that: the chemical formula of described BAPTA derivant is:
Wherein: X represents C
nH
2n+1, n=2-8, or C
nH
2n+1(OCH
2CH
2)
m, n=1-18, m=1-3;
E represents disodium or calcium;
A, B represents H, CHO, COOH, NO
2, NHR, CF
3, alkyl, halogen or alkoxyl,
Two phenyl ring are symmetric, or asymmetric.
5, the purposes of BAPTA according to claim 1 and derivant thereof, it is characterized in that: the mechanism of action of described BAPTA derivant is that calcium ion is the coupling connection factor that presynaptic membrane is excited and mediator release is necessary, noxious stimulation causes that the release of neurotransmitter is relevant with the activity of calcium electric conductance with the voltage-dependent on the synapse telolemma, the BAPTA derivant can reduce the endocellular liberation calcium concentration, alleviate or eliminate the effect of calcium overload, improve the pain threshold values, reduce the sensitivity of human body, play the analgesic effect thermostimulation or chemical stimulation.
6, the purposes of BAPTA according to claim 1 and derivant thereof is characterized in that: the clinical indication of described analgesic includes: headache, trigeminal neuralgia, dysmenorrhea, postoperative pain, cancer pain, visceral pain, post-herpetic neuralgia, phantom pain, HIV, pathological pain, the tolerance of morphine class medicine or addiction patient's the pain that multiple sclerosis is relevant, serious chronic intractable pain or clinical common pain disease.
7, the purposes of BAPTA according to claim 1 and derivant thereof is characterized in that: described BAPTA and derivant thereof are used to prepare analgesic, can be made into tablet, pill, capsule, injection or other suitable dosage forms.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910144754A CN101632653A (en) | 2009-08-31 | 2009-08-31 | BAPTA and application of derivant thereof in preparing analgesic drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910144754A CN101632653A (en) | 2009-08-31 | 2009-08-31 | BAPTA and application of derivant thereof in preparing analgesic drugs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101632653A true CN101632653A (en) | 2010-01-27 |
Family
ID=41592098
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910144754A Pending CN101632653A (en) | 2009-08-31 | 2009-08-31 | BAPTA and application of derivant thereof in preparing analgesic drugs |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110507642A (en) * | 2019-10-10 | 2019-11-29 | 天津医科大学 | The host receptor ANXA2 of targeting pili adhesin YadC is for improving emergency lower urinary tract infection |
| CN112807298A (en) * | 2021-04-08 | 2021-05-18 | 徐州医科大学 | Application of BAPTA-AM in preparing analgesic |
-
2009
- 2009-08-31 CN CN200910144754A patent/CN101632653A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110507642A (en) * | 2019-10-10 | 2019-11-29 | 天津医科大学 | The host receptor ANXA2 of targeting pili adhesin YadC is for improving emergency lower urinary tract infection |
| CN112807298A (en) * | 2021-04-08 | 2021-05-18 | 徐州医科大学 | Application of BAPTA-AM in preparing analgesic |
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Open date: 20100127 |