Synthesis And Effect On Expression Of The Gastric Mucosa Of EGF And EGFR In Rat With Gastric Ulcer

Peptic ulcer (PU) has an experience of a gastrointestinal mucosa and submucosa muscle necrosis in the pathological injury. It has to build a healing epithelial tissue and connective tissue. H2-receptor antagonists set up the H2-receptor selectively on the membrane so that the cell wall of cyclic amp (cAMP) is generated and reduced gastric acid secretion. H2 receptor antagonist not only is inhibited to histamine-stimulated acid secretion, but also the gastrin is partially inhibited and the acid secretion which stimulated by acetylcholine is inhibited. Epidermal growth factor (EGF) is the single-chain polypeptide with a 53 amino acid. They come from the submandibular gland mainly, duodenum Brunner gland, renal tubular cells, pancreas, thyroid and liver, etc. In the gastric mucosa low levels of EGF protein can be detected. EGF combined epidermal growth factor receptor (EGFR) play a role in biology importantly to hold integrity and repair mucosal injury.The pathogenesis of digestible ulcer and the cure function for H2-Receptor antagonists were described in this paper. The pharmacological peculiarity of H2-Receptor antagonists is described in much detail. The final product was identified by comparing to the spectrum data in literature. The primary amines (cyclopentamine、cyclohexylamine、methylamine、n-butylamine、isopropylamine、tert-butyl amine) were selected to design and synthesize a series of phenoxypropylamide on the basic theory of the principle of bioisosterism. N-{3-[3-(1-Piperidinymethyl)phenoxy]propyl}chloroacetamide was synthesized by a three-step reaction from m-hydroxybenzaldehyde. Phenoxypropylamine derivatives were then synthesized by the reaction of N-{3-[3-(1-Piperidinymethyl)phenoxy]propyl}chloro acet-amide with primary amines and then with oxalic acid to obtain their corresponding salts Their chemical structures were identified by 1H-NMR, 13C-NMR, and MS. All of them were not reported by other in chemical abstracts (CA).A number of phenoxypropylamines were synthesized. With regards to possible SAR, our preliminary assumption was to synthesize the compounds N-{3-[3-(1-piperidinylmethyl) phenoxy]propyl}methylaminoacetamide 5a and N-{3-[3-(1-piperidinylmethyl)phenoxy] propyl}n-butylaminoacetamide 5b by adding primary amine straight chains in order to enhance the ability of the molecules to inhibit gastric acid. We synthesized compounds N-{3-[3-(1-piperidinylmethyl)phenoxy]propyl}isopropylaminoacetamide 5c and N-{3-[3-(1-piperidinylmethyl)phenoxy]propyl}tertiarybutylaminoacetamide 5d by adding a branched chain primary amine in order to enhance the flexibility of the molecules. The compounds N-{3-[3-(1-piperidinylmethyl)phenoxy]propyl}cyclopentyaminoacetamide 5e and N-{3-[3-(1-piperidinylmethyl)phenoxy]propyl}cyclohexylaminoacetamide 5f are the H2-receptor antagonists.The protocol offers several advantages such as mild reaction conditions, short reaction times, easy isolation and good yields. They showed some potential effects on the inhibition of gastric juice.In the inhibiting the gastric acid secretion of guinea pig stomach mucous membrane study, we chooses roxatidine acetate as a positive drug and found that four of the target compounds have a higher or equal activity compared with the positive drug. One of them,5b is the best. At the same time, we found that substitute on phenoxypropylamines have effect on the acting time and its binding ability with the stomach cells.Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were introduced to study the relationship between the structure and activity of the compounds. Using the compound bioactivities we studied quantitative structure-activity relationship (QSAR) regular of the phenoxypropylamines by CoMFA computation. And we got the regular how the steric factor and electrostatic factor effect on the bioactivity. And we also predicted the model structure which will have more powerful bioactivity based on the regular. This regular will benefit the work of modifying the molecular to find the better H2-receptor as inhibitor in the future.We observed that the effects of on expressions of EGF and EGFR in rat with gastric ulcer. The promotion of peptic ulcer healing mechanism was discussed:48 Wistar rats were randomly divided into six groups, each with eight, namely:(1) Control group, to appropriate saline gavage. (2) Ulcer model control group, to appropriate saline gavage. From (3) to (5), 5b is the highest, middle and the low-dose group (28 mg/kg,14 mg/kg,7 mg/kg). (6) Positive control group with drug Ranitidine (27 mg/kg). From (2) to (6), rats were burned using acetic acid to prepare gastric ulcer model, the normal control group rats was not operationed.After rats had been lavaged with doses for 15 days, continuous intragastric administration in the last administration after fasting for 24 hours, free drinking water, the first 16 days will be broken cervical rats were sacrificed, drawing. HE staining of 5b for small acetate rat mucosa of the gastric ulcer healing the impact of immunohistochemical staining of gastric EGF and EGFR expression.1. HE staining of the rats ulcer formation and healing.Normal control group:the gastric antral wall of rat has structural ntegrity, glandular mucosa is neat, and there was no obvious inflammatory cell infiltration.Model group:Gastric telangiectasia, congestive, obvious focal bleeding. There are a large number of the interstitial infiltration of inflammatory cells, and some regional mucosal necrosis, exfoliated, local glands was damaged.Treatment group:ranitidine,5b small acetate for high-dose and the dose of mucosal ulceration were observed varying degrees of healing ulcer lesions have varying degrees of the surface epithelium new coverage, inflammatory cells decreased significantly, we can see that the nascent gland hyperplasia coverage ulcers and fibrous connective tissue, obviously at the bottom of ulcer formation of granulation tissue, vascular mild gastric expansion, congestive.2. Renewable rat gastric mucosal thickness, the muscularis mucosa defects of the results of comparison:Renewable thickness of the gastric mucosa statistical analysis shows that for 5b in small doses and high dose group, ranitidine group and the untreated group model has obvious significant difference, p<0.01.Comparing the muscularis mucosa defects of the statistical analysis showed that butylamine roxatidine derivate(BRD) small acetate for the high dose group, ranitidine group and group therapy model has obvious significant difference, p<0.01.3. Experimental gastric ulcer rat mucosa EGF and EGFR immunohistochemical staining: Immunohistochemical staining showed that the normal control group EGF and EGFR expression was weakly positive for small 5b high dose group and the positive drug Ranitidine group EGF and EGFR expression was significantly increased.5b for the small-dose group increased expression of EGF and EGFR not obvious. These data suggest that n-butylamine Jiluosha acetate for the treatment of small ulcer in the process, for the dose-dependent expression of EGF and EGFR, EGF and EGFR may be mediated by 5b for small acetate promote ulcer healing role.The rat model with gastric ulcer model is established successfully. The study for 5b found that for a small increase in acetate ulcer mucosal lesions and the surrounding renewable thickness, width decreased muscularis mucosa defects, and promote epithelial tissue regeneration capabilities, and improved weary scar repair. From the study of 5b we found that for a small increase in acetate ulcer mucosal lesions and the surrounding renewable thickness, width decreased muscularis mucosa defects, and promote epithelial tissue regeneration capabilities, and improved weary scar repair, Granulation tissue, there by stimulating the formation of microvascular, inhibit secretion of parietal cells, and stimulate the ulcer edge epithelial cell proliferation, differentiation, migration and increased mucosal blood flow, and enhance the mucosal regeneration glands function, and promote ulcer healing. We have concluded that 5b would be a kind of antiulcer drugs probably and potentially.