CN110664798A - Mu opioid receptor agonist and application thereof - Google Patents
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
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Abstract
The invention provides a mu opioid receptor agonist and application thereof, wherein the compound is a monomer compound of 3,3 ', 4 ', 5 ', 5,6,7, 8-octamethoxy brass, and the compound can act on a six-time transmembrane structure of a central mu opioid receptor, generates an inhibitory membrane potential by combining with the mu opioid receptor, hinders pain signal uplink conduction, plays an opioid analgesic role and further plays a stronger analgesic role. Can replace the traditional opium drugs and avoid the side effects of constipation, respiratory depression, dependence, addiction and the like.
Description
Technical Field
The invention belongs to the field of pharmacy, particularly relates to an opiate analgesic, and more particularly relates to a mu opiate receptor stimulant and application thereof.
Background
The majority of pain is currently treated clinically by the use of opioids, most of which act through the mu opioid receptor encoded by the OPRM1 gene. They are effective in relieving pain, but are limited to some extent by side effects such as constipation, respiratory depression, dependence and addiction. Studies have shown that the mu opioid receptor gene can undergo extensive splicing, collectively referred to as OPRM1 and its splice isoforms, to produce a variety of mrnas encoding a number of proteins with different functions. These shear isomers help explain the clinical variability of patients' response to mu opioids. Opioids have been used for centuries to treat pain and include opium, which contains various alkaloids such as morphine and codeine. Mu opioid receptors belong to the family of G protein-coupled receptors (GPCRs), and studies to date have shown that 29, 16 and 19 splice isomers are derived from the OPRM1 gene of mice, large and human, respectively, and that certain similarities exist in the structure. These shear isomers can be broadly classified into three groups according to their structures: (1) a full sequence seven-transmembrane structure with a carboxy terminus (C-), 7-TM; (2) a sheared six-pass transmembrane structure, 6-TM; (3) sheared, single-pass transmembrane structure, 1-TM.
Pharmacological research shows that the side effect of opioid is closely related to the existence of a large number of different shearing isomers in vivo, wherein 6 transmembrane shearing isomers generated by the different shearing of the N end of a mu opioid receptor are analgesic targets without the side effect of the traditional opioid, and isomers generated by the different shearing of the C end of the mu opioid receptor are closely related to drug tolerance, addiction, skin pruritus and constipation caused by morphine. There are studies demonstrating the pharmacological significance of the mouse 6-TM splice isomer in the analgesic effect of IBNtxA and identifying receptor functional associations corresponding to the transmembrane structures encoded by exons 2 and 3. Thus, the 6-TM scissoring isomer provides a potential therapeutic target for different types of analgesics that are effective against different pain models without the side effects associated with traditional opioids.
Disclosure of Invention
The invention aims to solve the problem that an agonist acting on mu opioid receptors is provided aiming at the serious side effect caused by the traditional opioid drugs and no effective intervention treatment means. Further, the invention also provides application of the mu opioid receptor agonist as an analgesic.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a mu opioid receptor agonist having the structural formula shown in formula I:
the invention also provides application of the compound shown in the formula I in preparing analgesic drugs.
In particular, the compounds are drugs that act on the mu opioid receptor.
More specifically, the compound is a drug acting on a six-transmembrane structure of a mu opioid receptor.
Further, the invention provides an analgesic drug which takes a compound shown as the following formula I as an active ingredient,
the analgesic medicine comprises the active ingredients and auxiliary materials or carriers which are acceptable in medicine, and the active ingredients and the auxiliary materials or carriers which are acceptable in medicine are prepared into powder, tablets, injection, capsules or oral liquid together.
Has the advantages that:
the invention provides a new application of a monomer compound 3,3 ', 4 ', 5 ', 5,6,7, 8-octamethoxy brass (British name exoticin, CAS: 13364-94-8) in preparing analgesic drugs, and experiments show that the compound can act on a six-time transmembrane structure of a central mu opioid receptor, and can generate an inhibitory membrane potential by combining with the mu opioid receptor, so that the compound can block the ascending conduction of pain signals and play an opioid analgesic role, thereby playing a stronger analgesic role. Can replace the traditional opium drugs and avoid the side effects of constipation, respiratory depression, dependence, addiction and the like.
Drawings
The foregoing and/or other advantages of the invention will become further apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.
FIG. 1 is a graph of the effect of exoticin on a CFA pain model under thermal stimulation following peripheral and central administration of β -FNA.
FIG. 2 is a graph of the effect of exoticin on a model of CFA pain under mechanical stimulation following peripheral and central administration of β -FNA.
FIG. 3 shows the hot plate pain threshold results of the mice in each group.
FIG. 4 shows the results of mechanical pain threshold in the mice of each group.
FIG. 5 shows the results of measurement of constipation side effects of the mice in each group.
FIG. 6 shows the results of the determination of whether or not there is addiction or withdrawal side effect in each group of mice.
FIG. 7 shows the results of measurement of the presence or absence of respiratory depression side effects in each group of mice.
Detailed Description
The invention will be better understood from the following examples.
1. Laboratory mice and groups
The week-old WT mice used in this experiment were approximately 8-10 weeks old, and had weights of 20-25g, mE7b mice were mu opioid receptor gene-knockout model mice, and E11 mice with mu opioid receptor gene-partial knockout (i.e., both 7-TM and 1-TM retained, and 6-TM deleted) were provided by the American Memorial Sloan-Kettering cancer center, and were grouped as needed: the test was conducted in a quiet environment in the behavioral test of 6 mice in the WT + exocidin group, mE7b + exocidin group, E11+ exocidin group, and WT + morphine group (WT + Mor group). beta-FNA is a mu opioid receptor antagonist, and the analgesic effect of exoticin was explored by peripheral and central administration. The specific groups are WT group, WT + exoticin + beta-FNA (peripheral) group and WT + exoticin + beta-FNA (central) group. All mice were started with 20ul CFA given to the right hind sole and molded.
2. Behavioral experiments
2.1 mouse Hot plate experiment
Both mouse training and behavioral determination were performed at 8-12 am. Mice were acclimated in a plexiglas box with a smooth bottom for about 10min each time for 3 consecutive days before determining the basal thermal pain threshold of the mice. In a quiet environment at room temperature of 22. + -. 1 ℃ the instrument temperature was set to 55. + -. 0.5 ℃ in advance. After the temperature is stable, the mouse is placed in an organic glass box with a smooth bottom, and the time for causing the mouse to contract or lick the hindpaw is the mouse Paw-contracting latency (PWL), namely the thermal pain threshold. The incubation period for the hot plate to cause paw withdrawal in normal mice was 10-15s, and the average of three measurements was taken at 10min intervals. To prevent the mice from being scalded, the upper limit of PWL is 30 s. The mechanical paw withdrawal reflex threshold value of each group of mice is measured as a baseline value 2h after molding, the mice are dosed after baseline measurement, and the change of the mechanical paw withdrawal reflex threshold value of each group of mice is measured and observed again at 2h, 4h, 8h, 12h and 24h after dosing. The analgesic effect was calculated using the following formula: maximum possible effect MPE% — 100 × (measured reaction time-baseline reaction time)/(30-baseline reaction time).
2.2 mechanical stimulation experiment of mice
Both mouse training and behavioral determination were performed at 8-12 am. Before measuring the basic mechanical pain threshold of the mice, the mice are placed in an organic glass box with a grid bottom for adapting to the environment for 3 days continuously, and each time lasts for at least 20 min. According to the classical method, a mouse is placed in an organic glass box with a grid at the bottom in a quiet environment, after 20min adaptation, von Frey fiber filaments vertically stimulate the skin of the middle part of the right hind paw of the mouse, and the reaction of rapid rising, avoidance, licking and the like of the tested paw is observed to be regarded as positive reaction. Stimulating for 3-5 times, wherein each time is 1-2 seconds, and the interval between the two times is 5 s. If 3 times of stimulation cause the mouse to generate the foot-shortening reaction, the weight corresponding to the 3 times of stimulation is the mechanical foot-shortening reflex threshold value of the mouse. The mechanical paw withdrawal reflex threshold value of each group of mice is measured as a baseline value 2h after molding, the mice are dosed after baseline measurement, and the change of the mechanical paw withdrawal reflex threshold value of each group of mice is measured and observed again at 2h, 4h, 8h, 12h and 24h after dosing. The analgesic effect was calculated using the following formula: maximum possible effect MPE% — 100 × (measured reaction time-baseline reaction time)/(16-baseline reaction time).
3 analysis and discussion of behavioural results
3.1Exoticin exerts analgesic effects through central mu opioid receptors
As shown in fig. 1, 2 hours after injecting exoticin, the peripheral application of β -FNA did not affect the performance of mice in the hot plate experiment, MPE values were not significantly different from WT + exoticin group, but central administration of β -FNA significantly reduced the analgesic effect of exoticin, and there were statistical differences as compared to WT + exoticin group and WT + exoticin + β -FNA (peripheral) group, (P <0.05 and #, P < 0.05); 4 hours after exoticin injection, peripheral administration of beta-FNA still cannot influence the analgesic effect of exoticin, central administration of beta-FNA still can obviously reduce the analgesic effect of exoticin, MPE values are statistically different from that of a WT + exoticin group and a WT + exoticin + beta-FNA (peripheral) group, and the trend is consistent with the time point of 2 hours; at the 8h time point, the analgesic effect of the WT + exoticin + beta-FNA (peripheral) group is remarkably reduced as compared with that of the WT + exoticin group, the analgesic effect of the WT + exoticin + beta-FNA (Central) group is also reduced and is close to the baseline level, but the statistical difference between the WT + exoticin + beta-FNA (Central) group and the WT + exoticin + beta-FNA (peripheral) group and the WT + exoticin group still exists. Finally, the analgesic effect of WT + exoticin + β -FNA (Central) group, WT + exoticin + β -FNA (peripheral) group, and WT + exoticin + β -FNA (peripheral) group disappeared at 12h and 24h after the injection of exoticin.
As shown in fig. 2, the mechanical stimulation ethological results show that the peripheral administration of β -FNA at 2h, 4h, 8h, 12h and 24h after exocidin treatment did not have a significant effect on the analgesic effect of exocidin, i.e., the mean values and trends of WT + exocidin + β -FNA (peripheral) group and WT + exocidin group were consistent in the thermal stimulation experiment; the results of the β -FNA central administration show that the β -FNA central administration does not block the analgesic effect of exoicin at the time point of 2h, although the threshold value is reduced to some extent, the difference does not have statistical significance compared with the WT + exoicin group and the WT + exoicin + β -FNA (peripheral) group, while the threshold value is reduced to some extent at the time point of 4h, and the statistical difference occurs when the threshold values of the WT + exoicin group and the WT + exoicin + β -FNA (peripheral) group are almost constant, (# P <0.05 and, P < 0.05'); finally, at the three time points 8h, 12h, and 24h, exoticin had no analgesic effect, showing that the thresholds of the three groups were at baseline levels.
The results show that the analgesic effect of the exoticin is almost not influenced by using the beta-FNA at the periphery, and the analgesic effect of the exoticin is quickly reduced by using the beta-FNA at the center, so that the target point of the exoticin playing the analgesic effect is mainly present in the central mu opioid receptor.
3.2Exoticin exerts analgesic effects mainly through the 6-transmembrane structure of the central mu opioid receptor
As shown in the results of the thermal stimulation experiment in FIG. 3, 2 hours after exoticin treatment, the WT, mE7b and E11 mice can produce analgesic effect, but the analgesic effect obtained by the WT mice is obviously better than that obtained by the mE7b mice and the E11 mice, and compared with the E11 mice, the difference of the analgesic effect of the mE7b mice is not statistically significant, and the 6-time transmembrane structure of the mu opioid receptor is proved to have important effect on the analgesic effect of the medicine. FIG. 4 the results of mechanical stimulation also show that 2 hours after exoticin treatment, analgesic effect was observed in 3 groups of mice, with a clear statistical difference (P <0.05) compared to baseline. At four time points of 4 hours, 8 hours, 12 hours and 24 hours after exoticin treatment, exoticin has no analgesic effect on mice with two genotypes of mE7b and E11 mice, and the analgesic effect of mE7b mice has no statistical significance compared with that of E11 mice, and the fact that 6-time transmembrane structures of mu opioid receptors play an important role in exerting the analgesic effect of drugs is also proved.
4. Detection and result analysis of side effects associated with traditional opioids
4.1 determination of the Presence of Constipation side effects of drugs in mice
The side effect of constipation in mice was determined by fecal accumulation. After administration, the mice are respectively placed in boxes provided with filter screens, and quiet paper is placed at the bottom of the boxes to facilitate the collection of excrement. Feces were collected from both groups of mice after administration, once per hour, and continuously for 6 hours. The results are shown in FIG. 5. The data of the WT + exocidin group and the WT + morphine group (WT + Mor group) are significantly different, and it can be seen from the figure that the mice show constipation symptoms (P <0.05) 1 hour after morphine administration, and the constipation degree of the mice in the morphine group is increased with time, while the constipation tendency of the mice in the WT + exocidin group is not shown, compared with the WT + exocidin group. The above results demonstrate that the drug has no side effects of constipation.
4.2 determination of drug addiction or withdrawal side effects in mice
The jumping times of mice injected with naloxone in the abdominal cavity in a fixed space is an effective means for reflecting the addiction or withdrawal condition of the drug. In the research, the drug is injected into the abdominal cavity with 1mg/kg naloxone to finish whether the drug has addiction or withdrawal reaction. Naloxone is a potent, high affinity opioid receptor antagonist that simultaneously relieves both opioid overdose and postoperative respiratory depression and is often used to determine the degree of drug abuse in drug addicts. Naloxone was injected into mice in this study to promote withdrawal from the jump reaction. After 5 days of continuous administration, the number of jumps in 15 minutes was measured in the mice, and the results shown in fig. 5 were obtained. Mice in WT + exocidin group and WT + morphine group (WT + Mor group) were administered 3 hours after the last day, and were injected with 1mg/kg naloxone intraperitoneally to perform acute withdrawal experiments, and the average value was obtained by recording for 15min, counting the jumps of the mice. The results in fig. 6 show that the data for the WT + exoticin group and the WT + morphine group (WT + Mor group) are significantly different (P <0.05), i.e., the mice have significant addiction and withdrawal response after morphine administration, while the WT + exoticin group shows no withdrawal symptoms, indicating that the drug has no addiction or side effects of withdrawal.
4.3 determination of whether there is respiratory depression side effect of drugs on mice
The mouse respiratory depression was measured as the mouse respiratory rate and tidal volume. The mouse respiratory rate system (Buxcofine Pointe) records the relevant parameters of mouse respiration. Individual mice, not anesthetized, were placed in the canister to allow autonomous activity in the canister. The air pressure in the cylinder is calibrated before each use. Mice were acclimated to the test room prior to the experiment and baseline respiratory parameters were recorded for 30 minutes. Then the mice are taken out for administration and put into a cylinder to continuously monitor the change degree of the respiratory frequency of the mice after administration. The results are shown in FIG. 7. FIG. 7-A is a representative graphical representation of the respiratory rate within 1-2 hours after administration of saline or normal saline to each group of mice. From the graph a, it can be seen that the respiratory rate and minute tidal volume of the mice were significantly reduced compared to the control group after morphine administration, indicating that morphine has a significant inhibitory effect on the respiration of the mice. After the WT + exoticin group mice are given the drug, the respiratory rate of the mice does not show a significant decrease trend, and the related statistical results are shown in FIGS. 7-B and 7-C. The above results indicate that the drug does not cause the side effects of respiratory depression in mice.
While the present invention provides a mu opioid receptor agonist and its use, and methods and means for practicing the same, it is to be understood that the foregoing is merely a preferred embodiment of the present invention and that modifications and adaptations may be made by those skilled in the art without departing from the principles of the present invention and are intended to be within the scope of the present invention. All the components not specified in the present embodiment can be realized by the prior art.
Claims (7)
1. A mu opioid receptor agonist characterized by: it has a structural formula shown in formula I:
2. the use of a compound of formula I:
3. use according to claim 2, characterized in that: the compounds are drugs acting on mu opioid receptors.
4. Use according to claim 3, characterized in that: the compound is a drug acting on a six-transmembrane structure of a mu opioid receptor.
5. An analgesic drug characterized by: it takes a compound shown as the following formula I as an active ingredient,
6. the analgesic drug of claim 5, wherein: it also comprises pharmaceutically acceptable adjuvants or carriers with the active ingredient.
7. The analgesic drug of claim 6, wherein: it is powder, tablet, injection, capsule or oral liquid prepared from the active component and medically acceptable auxiliary materials or carriers.
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| CN116789765A (en) * | 2023-06-30 | 2023-09-22 | 湖南中晟全肽生化有限公司 | Polypeptide for activating receptor encoded by OPRM1 gene and application thereof |
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Non-Patent Citations (2)
| Title |
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| SHAFIULLAH SHAJIB等: "Polymethoxyflavones from Nicotiana plumbaginifolia (Solanaceae) Exert Antinociceptive and Neuropharmacological Effects in Mice", 《FRONTIERS IN PHARMACOLOGY》 * |
| 刘岸龙: "基于μ阿片类受体（OPRM1）及其剪切异构体研究电针和多甲氧基黄酮镇痛机制", 《中国博士学位论文全文数据库》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116789765A (en) * | 2023-06-30 | 2023-09-22 | 湖南中晟全肽生化有限公司 | Polypeptide for activating receptor encoded by OPRM1 gene and application thereof |
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