CN116983314B - Application of D1-like receptor agonist in preparation of gastric motility enhancing drugs - Google Patents
Application of D1-like receptor agonist in preparation of gastric motility enhancing drugs Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- Veterinary Medicine (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The invention relates to the technical field of dopamine receptor agonists, in particular to application of a D1-like receptor agonist in preparation of a medicine for enhancing gastric motility. The D1-like receptor agonist is SKF 38393. The invention provides a D1-lie receptor agonist SKF38393 for preparing a medicine for enhancing gastric motility, and provides more choices for the development of medicines for treating and/or preventing gastric motility disorder.
Description
Technical Field
The invention relates to the field of novel application of medicines, in particular to application of a D1-like receptor agonist in preparation of medicines for enhancing gastric motility.
Background
Dopamine (DA) is an important catecholamine substance regulating gastrointestinal motility and is widely distributed in the central and digestive tracts. The research shows that various diseases related to gastrointestinal motility disorder have abnormal digestive tract DA energy system, such as parkinsonism gastroparesis, functional dyspepsia and the like. Symptoms caused by the diseases are one of the most common reasons for repeated medical seeking of patients, and seriously affect national physical and psychological health and social development.
DA receptors include D 1 、D 2 、D 3 、D 4 And D 5 Five subtypes, which exhibit a high degree of similarity in the original amino acid sequence, have 7 common transmembrane domains,coupled to different subtypes of G protein, thereby inducing different intracellular signaling mechanisms. Based on their structural, pharmacological and biochemical properties, these receptors are classified as D1-like family (D1-like family, including D 1 And D 5 Receptors) or D2-like family (D2-like family, including D 2 、D 3 And D 4 Receptors) coupled to Gs proteins that, upon activation, stimulate adenylate cyclase activation (adenylate cyclase, AC) to increase intracellular cyclic adenosine monophosphate (cAMP) levels; the latter is coupled to the Gi protein and, upon activation, inhibits AC activity, resulting in a decrease in intracellular cAMP levels. The D2-like family also inhibits L-type calcium channels and reduces Ca 2+ And (3) internal flow.
The research shows that DA can relax smooth muscle of the fundus of the stomach, strengthen the relaxation of the fundus of the stomach, reduce the compliance of the intragastric pressure and the gastroduodenal, inhibit the advancing movement of food from the stomach body to the antrum of the stomach, delay the gastric emptying, microinjection of DA into the movement complex of the vagus of the rat can reduce the tension of the stomach in the body and inhibit the phase contraction, and the effect can be realized by the ipsilateral vagal nerve cutting or the addition of D to the ventricle 2 Blocking by receptor blocker suggests that the inhibition of gastric motility by DA is due to D 2 Receptor mediated. Thus some D 2 The receptor blocker anti-dopaminergic prokinetic agent such as bripiride, domperidone, etc. is used for treating various diseases or symptoms related to upper gastrointestinal motility disorder, such as functional dyspepsia, gastric retention and emesis caused by various reasons. However, the results of later evidence-based medical studies indicate that the above drugs do not produce their earlier-stated effects of treating gastric motility disorders. From previous studies, it can be seen that there is currently no clear conclusion as to what mechanism DA regulates gastric motility. Therefore, on the basis of further researching the action mechanism of DA on gastric motility regulation by scientific researchers, developing more medicaments with better effects for enhancing gastric motility is still a technical problem in the field.
Disclosure of Invention
In order to solve the above problems in the prior art, the present inventors have mainly aimed at providing the use of D1-like receptor agonists in the preparation of drugs for enhancing gastric motility.
In order to achieve the above purpose, the present invention provides the following technical solutions:
the D1-like receptor agonist is SKF38393 or pharmaceutically acceptable salt thereof, and the structural formula of SKF38393 is shown in the following formula I:
formula I.
Preferably, the D1-like receptor agonist is used in the preparation of a medicament for treating functional dyspepsia, gastroparesis syndrome or postoperative abdominal distension.
For functional dyspepsia (Functional Dyspepsia, FD), a disease that severely affects the daily activities of patients, the main symptoms include postprandial fullness, early satiety, bloating, burning sensation, etc., often dominated by one or a group of symptoms. Symptoms can change in the course of the disease, the onset of the disease is slow, and the disease is frequently repeated. Typical symptoms include upper abdominal pain, feeling of fullness, loss of appetite, eructation, and some patients have symptoms such as anxiety, insomnia, depression, headache, inattention, etc. Complications also occur in some patients: anxiety, autonomic nerve dysfunction symptoms such as palpitations, hand tremble, sweating, frequent urination, etc.
For gastroparesis syndrome (Gastroparesis Syndrome), a group of clinical symptoms characterized by delayed gastric emptying. And no organic lesions of the upper digestive tract or upper abdomen were found in the examination. Two types can be distinguished according to etiology, primary and secondary. Primary gastroparesis, also known as idiopathic gastroparesis, is frequently found in young women. The gastroparesis can be classified into acute and chronic according to the duration of the disease. Clinically chronic conditions are common, with symptoms lasting or repeatedly occurring for several months or even more than 10 years. The disease is often manifested as dyskinesia to gastroparesis in clinical manifestations: 1. gastric sinus hypomotility and delayed gastric emptying. 2. The proximal stomach compliance is reduced, which results in reduced gastric accommodations. 3. The pressure at the proximal end of the stomach is reduced, so that gastric fluid emptying is delayed. 4. The stomach, pylorus and duodenum are not in coordination with each other. Thus, the disease is mainly manifested as delayed gastric emptying. Symptoms such as early satiety, postprandial upper abdominal distention, and discomfort of the upper abdomen after eating are common.
For abdominal distension after operation, abdominal distension is one of the most common and earliest symptoms after abdominal operation, and is caused by weakening or disappearance of intestinal peristalsis after operation due to anesthetic and operation, generally, the abdominal distension can be recovered by itself after operation for about 48 hours, but in some cases, the abdominal distension has long duration and is not easy to recover, so that incision healing is affected, discomfort is brought to patients, oral medicines and intramuscular injection are generally adopted clinically, the treatment effect is not ideal, gastrointestinal decompression and anal canal air discharge methods are adopted, and the operation is complicated, so that the pain of intubation is brought to the patients; or intestinal adhesion and intestinal obstruction can occur after the duration of abdominal distention is long, and the operation is performed again.
Preferably, the D1-like receptor agonist is mediated by the enteric neurocholinergic pathway.
The use of the invention, the D1-like receptor agonist, a pharmaceutically acceptable salt thereof, is administered alone or in combination with one or more other therapeutic agents. The therapeutic agent can be a traditional Chinese medicine, a chemical medicine or a biological medicine.
The invention also provides application of the pharmaceutical composition in preparing medicines for enhancing gastric motility, wherein the composition comprises a compound shown in a formula I, pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, diluents or carriers.
Preferably, the pharmaceutical composition is in the form of capsule, powder, tablet, granule, pill, injection, oral liquid, inhalant, ointment, suppository or patch.
The D1-like receptor agonists of the present invention may also be used in combination with one or more other therapeutic agents, either sequentially or simultaneously.
Preferably, the dosage of SKF38393 in the composition is 0.1-100mg.
Further preferred, the dosage of SKF38393 or a pharmaceutically acceptable salt thereof in the composition is 0.5-50mg.
The invention has the main beneficial effects as follows:
the invention provides a D1-lie receptor agonist SKF38393 for preparing a medicine for enhancing gastric motility, and provides more choices for the development of medicines for treating and/or preventing gastric motility disorder.
Drawings
FIG. 1 is a graph of the effect of DA on normal rat stomach ex vivo smooth muscle.
Wherein FIG. 1A shows that the in vitro smooth muscle strips of the stomach of a normal rat are 1.0X10 -9 -1.0×10 -5 A contraction curve under the DA action of a mol/L concentration range; FIG. 1B shows that the in vitro smooth muscle strips of the stomach of a normal rat are 1.0X10 -9 -1.0×10 -5 DA in the mol/L concentration range;
FIG. 1C shows SKF38393 at 1.0X10 -7 -3.0×10 -5 The ratio of the dynamic index of myobar contraction under the action of the mol/L concentration range to the basal state; FIG. 1D shows that Quinpirone is at 1.0X10 -9 -1.0×10 -5 The ratio of the dynamic index of myobar contraction under the action of the mol/L concentration range to the basal state; n=8 ×p<0.05，**p<0.01。
FIG. 2 is a graph showing the effect of DA on in vitro smooth muscle in normal rats in the case of pretreatment of TTX and atripine.
Wherein FIGS. 2A, 2B and 2C are respectively 1.0X10 of isolated smooth muscle strips of normal rat stomach in normal pretreatment of TTX and atropine -9 -1.0×10 -5 A contraction curve under the DA action of a mol/L concentration range;
under the conditions that 2D and 2E are respectively the pretreatment TTX and atripine, the in-vitro smooth muscle strips of the normal rat stomach are 1.0 multiplied by 10 -9 -3.0×10 -6 The ratio of the kinetic index of myobar contraction to basal state upon DA action at the concentration range of mol/L. n=8 ×p<0.05，**p<0.01，***p<0.001。
FIG. 3 is a graph showing the effect of SKF38393 on the in vitro smooth muscle of the stomach of normal rats in the case of pretreatment TTX and atripine.
Wherein FIGS. 3A, 3B and 3C are respectively 1.0X10 of isolated smooth muscle strips of normal rat stomach in normal pretreatment of TTX and atropine -9 -1.0×10 -5 The shrinkage curve under the action of SKF38393 in the concentration range of mol/L. Under the conditions that 3D and 3E are respectively pretreated TTX and atripine, SKF38393 with the concentration range of 1.0X10-9-1.0X10-5 mol/L of normal rat gastric in vitro smooth muscle strip is usedThe ratio of the kinetic index of muscle contraction to the basal state when in use. n=8, p<0.05，**p<0.01。
Detailed Description
Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be within the scope of the present invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that variations and modifications can be made in the methods and applications described herein, and in the practice and application of the techniques of this invention, without departing from the spirit or scope of the invention.
The raw materials or auxiliary materials used in the invention are available in the market unless otherwise specified.
The invention is further illustrated by the following examples.
Experimental example 1
Experimental medicine:
Dopamine hydrochloride (DA) ；
SKF38393 (D1-like receptor agonist);
quinpirole (D2-like receptor agonist);
the experimental steps are as follows:
the tension signal transduction system records the gastric motility experimental steps:
SD rats were fasted 1 night in advance, euthanized using carbon dioxide inhalation, the abdomen was cut, the stomach was rapidly removed, the stomach contents were rinsed with K-HS, cut along the greater curvature of the stomach, the mucosal layer was laid flat on silica gel, the mucosa and submucosa were carefully cut off under the stereoscope with microscopic scissors, and the entire procedure was completed on ice. The smooth muscle layer is cut into muscle strips with the width of 1-2mm and the length of 9-11mm along the longitudinal muscle, the two ends of the muscle strips are tied by surgical suture, one end of the smooth muscle layer is fixed at the bottom of the bath tank, and the other end of the smooth muscle layer is hung on the pressure transducer. The muscle strips were placed in 5mL of K-HS with constant temperature (37.+ -. 0.5 ℃), continuous aeration (95% oxygen and 5% carbon dioxide). After resting tension of 1mN is applied to muscle strips, the muscle strips are balanced in a water bath for about 30 minutes, tool drugs such as DA or DA receptor agonist with specific concentration are added after the base line is stabilized, the curve is observed and recorded for 8-10 minutes after each drug addition is stabilized, and the muscle strips are washed three times and are balanced again.
Experimental results:
binding showed that treatment of rat stomach ex vivo smooth muscle strips with exogenous DA, when at lower concentrations (1.0X10 -9 -3.0×10 -8 mol/L), the myobar contraction amplitude is enhanced; and when the DA concentration is higher (1.0X10) -7 -1.0×10 -5 mol/L), the contraction amplitude of muscle strips is reduced, and the contraction frequency is not changed obviously (as shown in figure 1A of figure 1&B，n=8，*p<0.05，**p<0.01). Similar to DA at low concentrations, the D1-like receptor agonist SKF38393 (1.0X10) -7 -3.0×10 -5 mol/L) also causes an increase in the amplitude of the contraction of the rat gastric ex vivo smooth muscle (fig. 1c, n=8,p<0.05 The effect is dose-dependent and has no obvious effect on the contraction frequency; whereas the D2-like receptor agonist quinpirole (1.0X10) -9 -1.0×10 -5 mol/L) has a tendency to inhibit the contraction amplitude of the rat stomach in vitro smooth muscle (FIG. 1D), and has no obvious influence on the contraction frequency.
As shown in FIG. 2, the effect of DA on the in vitro smooth muscle of the stomach of normal rats in the case of pretreatment of TTX and Atropine was further studied, as shown in FIGS. 2A, 2B and 2C, which are respectively 1.0X10 of in vitro smooth muscle strips of the stomach of normal rats in the case of pretreatment of TTX and Atropine -9 -1.0×10 -5 The contraction curve under DA action in the concentration range of mol/L shows that when the sodium channel blocker TTX is pretreated at a concentration of 1.0X10-5 mol/L, respectively (FIG. 2B)&D，n=8，**p<0.01，***p<0.001 And M receptor blocker atripine (FIG. 2C)&E，n=8，*p<0.05，**p<0.01 The excitation of the amplitude of contraction of the gastric smooth muscle by DA can be blocked, whereas the inhibitory effect of the high concentration of DA on the amplitude of contraction of the smooth muscle is not affected. Also, the process of the present invention is,
the effect of SKF38393 on normal rat stomach ex vivo smooth muscle was examined under pretreatment TTX and atripine. As shown in FIGS. 3A, 3B and 3C, the normal rat stomach in vitro smooth muscle bars were in.0X10 s when TTX and atropine were pretreated normally -9 -1.0×10 -5 The shrinkage curve under the action of SKF38393 in the concentration range of mol/L.
At TTX (fig. 3b & D, n=8, p <0.05, p < 0.01) and atropine (fig. 3c & e, n=8, p < 0.05) pre-treatment concentrations, respectively, the excitatory effect of D1-like receptor agonist SKF38393 on gastric smooth muscle could be completely blocked.
The prophase speculation was also verified by the above experiments: the mechanism of action of low concentrations of DA and D1 receptor agonists on rat gastric smooth muscle is identical and is mediated through the cholinergic pathways of the enteric nervous system.
Experimental example 2
The effect of the drug SKF38393 on gastric motility was evaluated by observing the effect of SKF38393 on gastric emptying in atropine loaded mice.
72 mice were taken, 18-22g each of which had a half of the male and female. Mice were randomized into 6 groups, namely, a blank control group, a model control group, a positive control group, a SKF38393 low dose group (0.3 mg/kg), a SKF38393 medium dose group (0.6 mg/kg), and a SKF38393 high dose group (1.2 mg/kg). Mice were dosed by gavage for 3 days, and mice were fasted for 12 hours without water withdrawal prior to the last dose, and were dosed by gavage with the test drug, and the blank control group and the model control group were gavaged with equal volume of physiological saline, and the positive control group was gavaged with positive control drug PF-2562. After 20 minutes of administration, other groups except for a blank control group were intraperitoneally injected with atropine 0.5mg/kg, after 40 minutes, each group of mice was perfused with semi-solid nutritional foodstuff (10 g of carboxymethyl cellulose CMC was dissolved in 250mL distilled water, 16g of milk powder, 8g of white granulated sugar, 8g of starch were respectively added, stirred uniformly, and finally 300mL of semi-solid paste was prepared, the mixture was refrigerated in a refrigerator for later use, heated to room temperature in a water bath before use), the animals were sacrificed after 20 minutes, the abdominal cavity was dissected, the pylorus and the cardia were dissected, the whole stomach was taken, the whole stomach was weighed by an electronic balance after wiping with filter paper, the stomach was cut off to a large curve, the stomach content was washed out and dried by filter paper after wiping with the stomach, and the net stomach was weighed. The difference between the total stomach weight and the net stomach weight is the residual stomach amount, and the comparison is carried out between groups. Wherein, when the mice are ill or dead, the mice are removed; mice were rejected when their test data were not within statistically trusted intervals. The results are shown in Table 1 below.
TABLE 1 effect of SKF38393 on gastric emptying in atropine loaded mice
P <0.05 compared to the blank; comparison with model group #p <0.05, #p <0.05.
As can be seen from the experimental results in Table 1, SKF38393 has a remarkable promoting effect on gastric emptying of atropine loaded mice. And the promoting effect is better than that of positive medicine PF-2562.
The foregoing is merely a preferred embodiment of the invention, and it should be noted that modifications could be made by those skilled in the art without departing from the principles of the invention, which modifications should also be regarded as being within the scope of the invention.
Claims (6)
- Use of SKF38393 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of delayed gastric emptying, the SKF38393 having the structure shown in formula I below:formula I.
- 2. The use of claim 1, wherein the SKF38393 or pharmaceutically acceptable salt thereof is administered alone or in combination with one or more other therapeutic agents.
- 3. The use of claim 1, the medicament further comprising a pharmaceutically acceptable carrier.
- 4. The use according to claim 1, wherein the medicament is in the form of a capsule, powder, tablet, granule, pill, or oral liquid.
- 5. The use according to claim 1, wherein the SKF38393 or pharmaceutically acceptable salt thereof is in the amount of 0.1-100mg in the medicament.
- 6. The use according to claim 5, wherein the dosage of SKF38393 or a pharmaceutically acceptable salt thereof in the medicament is 0.5-50mg.
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| CN114344300A (en) * | 2014-05-16 | 2022-04-15 | 拉夸里亚创药株式会社 | 5-HT4 receptor agonists for gastroparesis |
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| EP0244088A2 (en) * | 1986-04-03 | 1987-11-04 | Smithkline Beecham Corporation | 1-Phenyl-3-benzazepine compounds and medicaments containing these compounds for treating gastrointestinal motility disorders |
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