CN113712965A

CN113712965A - N, N, N application of N' -tetra-group (2-benzyl) -acetamide in preparing medicine for treating UC

Info

Publication number: CN113712965A
Application number: CN202111110043.1A
Authority: CN
Inventors: 董辉; 卢骋; 万晗星; 杨仕明; 杨凤; 陈君
Original assignee: Second Affiliated Hospital Army Medical University
Current assignee: Second Affiliated Hospital Army Medical University
Priority date: 2021-09-18
Filing date: 2021-09-18
Publication date: 2021-11-30
Anticipated expiration: 2041-09-18
Also published as: CN113712965B

Abstract

The invention discloses application of N, N, N 'and N' -tetra-yl (2-benzyl) -acetamide in preparation of a medicine for treating Ulcerative Colitis (UC), wherein N, N, N 'and N' -tetra-yl (2-benzyl) -acetamide can relax mesenteric arterioles, so that mesenteric blood flow is restored, and the function of an intestinal mucosa barrier is maintained, thereby providing a new thought for treating UC and a new candidate medicine for treating UC.

Description

N, N, N application of N' -tetra-group (2-benzyl) -acetamide in preparing medicine for treating UC

Technical Field

The invention relates to the field of biological medicines, in particular to application of N, N, N 'and N' -tetra-yl (2-benzyl) -acetamide in preparation of a medicine for treating UC.

Background

Ulcerative Colitis (UC) is a global epidemic. In China, the number and incidence of UC patients tend to increase year by year. UC obviously affects the health level of people in China, and serious complications caused by UC can threaten the lives of patients. The existing medicines for treating UC are mainly divided into aminosalicylic acid medicines, glucocorticoid and biological agents and the like. These therapeutic agents are mostly used to control disease symptoms, require long-term or even lifelong administration, and have major drug side effects. The unclear pathogenesis of UC is an important reason for the current lack of effective therapeutic drugs.

The current drugs clinically used for treating UC mainly act on microorganisms and inflammatory cells in the intestinal tract to obtain limited efficacy of antibiosis and antiphlogosis. At present, new drug targets are urgently needed to be searched from different visual fields, and more effective therapeutic drugs are researched and developed. It is well known that the effective blood supply function of intestinal submucosal microvasculature plays a key role in maintaining normal mucosal barrier function and histological structure; in UC, however, the blood supply of the microvasculature under the intestinal mucosa is impaired. For example, the diastolic response of the submucosal microvasculature of the intestine to the vagal transmitter acetylcholine is impaired in patients with UC, resulting in a reduced blood flow supply in areas of chronic inflammation of the colon. This may lead, on the one hand, to a reduction in the capacity to remove inflammatory mediators, which may lead to local accumulation thereof, and, on the other hand, to a reduction in the capacity to repair the damaged intestinal mucosa in the area of chronic inflammation. Both will further aggravate the damage of intestinal mucosa cells and the loss of mucosa barrier function, thereby promoting the generation and development of UC. Therefore, the dysfunction of the microvascular function under the intestinal mucosa may be an important basis for the treatment difficulty of UC, and a drug for restoring the submucosal microvascular function is urgently needed to provide a new treatment means for clinically preventing and treating the treatment difficulty of UC.

Disclosure of Invention

In view of the above, an object of the present invention is to provide an application of N, N, N ', N' -tetra (2-benzyl) -acetamide in preparing a medicament for treating ulcerative colitis.

In order to achieve the purpose, the invention provides the following technical scheme:

n, N, N 'and N' -tetra-group (2-benzyl) -acetamide, wherein N, N 'and N' -tetra-group (2-benzyl) -acetamide have structural formula shown in formula I.

Preferably, the concentration of N, N, N ', N' -tetra-yl (2-benzyl) -acetamide is 5 mg/mL.

Preferably, the N, N, N 'and N' -tetra-yl (2-benzyl) -acetamide is applied to preparing the medicine for relaxing mesenteric arterioles.

Preferably, the N, N, N ', N' -tetra-yl (2-benzyl) -acetamide is used for preparing the medicine for restoring the body weight or the colorectal length of an ulcerative colitis animal.

The invention has the beneficial effects that: n, N, N 'and N' -tetra-yl (2-benzyl) -acetamide for treating UC, and can restore mesenteric blood flow and maintain intestinal mucosa barrier function through its relaxation to mesenteric arteriole, thereby providing new idea for UC treatment.

Drawings

In order to make the object, technical scheme and beneficial effect of the invention more clear, the invention provides the following drawings for explanation:

FIG. 1 shows N, N, N 'the effect of N' -tetra-yl (2-benzyl) -acetamide (TPEN) in relaxing mesenteric arterioles (A: N, N, N ', N' -tetra-yl (2-benzyl) -acetamide (TPEN) in dose-dependent relaxation of Norepinephrine (NE) preshrinked mouse mesenteric arterioles; B: TPEN in dose-dependent relaxation of NE preshrinked but not KCl contracted mouse mesenteric arterioles);

FIG. 2 shows N, N, N 'and the effect of N' -tetra-yl (2-benzyl) -acetamide (TPEN) on UC in mice (A: body weight test result; B: colorectal length comparison; C: colorectal pathology section score ratio).

Detailed Description

The present invention is further described with reference to the following drawings and specific examples so that those skilled in the art can better understand the present invention and can practice the present invention, but the examples are not intended to limit the present invention.

N, N, N 'and N' -tetra-yl (2-benzyl) -acetamide in the present invention were obtained from MCE corporation (cat. No. HY-10448); DSS was purchased from MPbio, usa; MPO detection kits were purchased from Abcam, USA (cat # ab 105136).

Example 1

A method for in vitro relaxation of mouse mesenteric arterioles by using N, N, N 'and N' -tetra-yl (2-benzyl) -acetamide comprises the following specific steps:

A. after C57BL/6 mice were sacrificed by cervical dislocation, laparotomy and mesentery was excised and immediately immersed in ice-cold Krebs-Henseleit solution. Krebs-Henseleit solution contains (mM): 118mM NaCl, 4.7mM KCl, 1.18 mM MgSO₄、25mM NaHCO₃、1.2mM KH₂PO₄、1.6mM CaCl₂And 11.1mM D-glucose.

B. Mesenteric arterioles (superior mesenteric artery second branch, 2mm in length and 100 to 150 μm in diameter) were obtained under a microscope. They were removed from the surrounding adipose and connective tissue in Krebs-Henseleit solution and then mounted in a Mulvany-type wire electromyograph (model 520A, DMT, Ohwis, Denmark) for functional assessment. The Powerlab analysis system (AD instruments, Colorado Spprins, Colorado, USA) records changes in isometric tension. Two tungsten filaments (each 40 μm in diameter) were passed through the lumen of the microvessels and fixed to the jaws of an electromyograph. Krebs-Henseleit solution (5mL) was treated with 95% O at 37 ℃ at room temperature₂+5％CO₂The mixed gas of (a) is continuously aerated.

C. After arteriolar installation, the vessels were allowed to stabilize at zero tension for 20 minutes before normalization. After the equilibration period, the vessels were pre-contracted with 5 μ M Norepinephrine (NE), and after rinsing, various concentrations of N, N, N ', N' -tetrayl (2-benzyl) -acetamide were added for the experiments.

D. The results of the detection were statistically analyzed by Graphpad software (a in fig. 1). Statistics show that N, N, N ', N' -tetra-yl (2-benzyl) -acetamide was able to dose-dependently dilate mouse mesenteric arterioles (B in FIG. 1).

Example 2

A method for relieving mouse UC by using N, N, N 'and N' -tetra-yl (2-benzyl) -acetamide comprises the following steps:

A. c57BL/6 mice, 6 weeks old, were randomly divided into control and experimental groups. The control group received N, N, N ', N' -tetra-yl (2-benzyl) -acetamide (10 mg/kg/day, gavage), while the experimental group received 2.5% DSS in drinking water or a combination of 2.5% DSS plus N, N, N ', N' -tetra-yl (2-benzyl) -acetamide (10 mg/kg/day, gavage). All mice were treated for 7 days as experimental period and monitored daily throughout the experimental period by measuring body weight.

B. And (5) counting and analyzing the detection result by Graphpad software. Statistical results showed that N, N, N ', N' -diyl (2-benzyl) -acetamide was able to restore body weight and colorectal length in DSS-colitis mice (fig. 2, a, B); meanwhile, N, N, N 'and N' -tetra-yl (2-benzyl) -acetamide can also relieve the inflammatory degree of the colorectal cancer of DSS-colitis mice (figure 2, C).

N, N, N ', N' -tetra-yl (2-benzyl) -acetamide can therefore be used to treat ulcerative colon.

The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention. The protection scope of the invention is subject to the claims.

Claims

Use of N, N, N 'and N' -tetra-yl (2-benzyl) -acetamide for the manufacture of a medicament for the treatment of ulcerative colitis.
2. Use according to claim 1, characterized in that: the N, N, N 'and N' -tetra-yl (2-benzyl) -acetamide can be used for preparing medicines for relaxing mesenteric arterioles.
3. Use according to claim 1, characterized in that: the N, N, N ', N' -tetra-yl (2-benzyl) -acetamide is used for preparing a medicament for restoring the body weight or the colorectal length of an ulcerative colitis animal.