Application of N1-dihydrocaffeoyl-N10-caffeoyl spermidine in preparation of acetylcholin esterase inhibitor
N1-dihydrocaffeoyl-N10-caffeoyl spermidine, derived from Lycium ruthenicum and Lycium chinense, addresses the limitations of synthetic AChE inhibitors by effectively inhibiting AChE, offering a safer and more effective treatment for Alzheimer's, myasthenia gravis, and glaucoma.
Patent Information
- Application Number
- CN202510569477.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-03
- Publication Date
- 2025-07-15
AI Technical Summary
The existing synthetic acetylcholinesterase inhibitors have low bioavailability, central side effects and drug resistance after long-term drug use, and natural compounds have not been fully utilized in the development of acetylcholinesterase inhibitors.
Using N1-dihydrocaffeyl-N10-caffeylspermidine isolated from Lycium barbarum as the active ingredient, it was found that it significantly inhibited acetylcholinesterase activity through in vitro enzyme activity inhibition experiments, providing pharmaceutically acceptable salts for the preparation of acetylcholinesterase inhibitors.
It provides highly effective and low-toxic acetylcholinesterase inhibitors for the treatment of diseases such as Alzheimer's disease, myasthenia gravis and glaucoma, reducing the risk of toxic and side effects of the drug and expanding the development path of naturally-sourced AChE inhibitors.
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Figure CN120305237A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of medicinal chemistry, and specifically relates to the application of N1-dihydrocaffeoyl-N10-caffeoylspermidine in the preparation of acetylcholinesterase inhibitors. Background Art
[0002] Acetylcholinesterase (AChE) is a key enzyme widely distributed in the central nervous system, neuromuscular junctions, and cholinergic synapses. Its main function is to terminate cholinergic nerve signal transmission by hydrolyzing the neurotransmitter acetylcholine (ACh). The homeostasis of ACh is crucial for maintaining learning, memory, muscle contraction, and autonomic nerve function. When the activity of AChE abnormally increases, the decomposition of ACh accelerates, leading to a significant decrease in the level of ACh in the synaptic cleft, and then causing cholinergic neurotransmission disorders. This mechanism is closely related to the pathological processes of various diseases. For example, in Alzheimer's disease (AD), the increased activity of AChE in the brain is one of the core factors for cognitive function decline; in myasthenia gravis, the patient's own antibodies attack the ACh receptors at the neuromuscular junction, and the overactivity of AChE further exacerbates the signal transmission defect; in glaucoma, abnormal ChE activity may lead to apoptosis of retinal ganglion cells and accelerate optic nerve damage.
[0003] Based on this, AChE inhibitors have become an important treatment strategy for the above diseases by delaying the hydrolysis of ACh and increasing the concentration of ACh in the synapse. Although the currently clinically used synthetic AChE inhibitors (such as donepezil and rivastigmine) have certain efficacy, they have problems such as low bioavailability, central side effects (such as dizziness, gastrointestinal reactions), and drug resistance after long-term use. Therefore, the development of new, highly efficient, and low-toxic AChE inhibitors remains an important direction in current drug research and development.
[0004] Natural products have shown unique advantages in the development of AChE inhibitors due to their characteristics such as diverse chemical structures, high biocompatibility, and multi-target effects. Natural compounds (such as alkaloids and phenolic acids) often have complex skeletons that are difficult to simulate artificially. For example, galantamine from Lycoris radiata and berberine from Coptis chinensis have been proven to be potent AChE inhibitors and have been successfully applied in the treatment of AD. Many medicinal plants (such as Lycium barbarum and Alpinia oxyphylla) have been used in traditional medicine to improve cognitive function, and the screening of their active ingredients can significantly shorten the drug discovery cycle. Compared with synthetic compounds, natural source components have clear metabolic pathways and a lower risk of toxic side effects, making them more suitable for long-term medication needs.
[0005] The present invention isolates the monomeric active ingredient N1-dihydrocaffeoyl-N10-caffeoylspermidine from Lycium ruthenicum Murr. and Lycium barbarum L. Currently, there is little research on the biological activity of N1-dihydrocaffeoyl-N10-caffeoylspermidine, and there is no research on its inhibition of acetylcholinesterase. The present invention discovers for the first time that this compound has significant AChE inhibitory activity. This discovery not only provides a new structural template for natural source AChE inhibitors but also opens up a better drug development path for the treatment of diseases such as Alzheimer's disease. Summary of the Invention
[0006] Through preliminary in vitro enzyme activity inhibition experiments, the present invention finds that N1-dihydrocaffeoyl-N10-caffeoylspermidine can significantly inhibit the activity of acetylcholinesterase.
[0007] Therefore, the object of the present invention is to provide the use of N1-dihydrocaffeoyl-N10-caffeoylspermidine in the preparation of acetylcholinesterase inhibitors.
[0008] The second object of the present invention is to provide the use of the pharmaceutically acceptable salt of N1-dihydrocaffeoyl-N10-caffeoylspermidine in the preparation of acetylcholinesterase inhibitors.
[0009] The third object of the present invention is to provide the use of N1-dihydrocaffeoyl-N10-caffeoylspermidine in the preparation of drugs for treating diseases related to abnormal elevation of acetylcholinesterase.
[0010] The fourth object of the present invention is to provide the use of the pharmaceutically acceptable salt of N1-dihydrocaffeoyl-N10-caffeoylspermidine in the preparation of drugs for treating diseases related to abnormal elevation of acetylcholinesterase.
[0011] To achieve the above objects, the present invention adopts the following technical solutions: The use of N1-dihydrocaffeoyl-N10-caffeoylspermidine in the preparation of acetylcholinesterase inhibitors, wherein the structure of N1-dihydrocaffeoyl-N10-caffeoylspermidine is shown in formula (1): Formula (1).
[0012] N1-dihydrocaffeoyl-N10-caffeoylspermidine, molecular formula C 25 H 33N3O6, with a molecular weight of 471.24, full English name (E)-3-(3,4-dihydroxyphenyl)-N-(3-((4-(3-(3,4-dihydroxyphenyl)propanamido)butyl)amino)propyl)acrylamide, English abbreviation N1-dihydrocaffeoyl-N10-caffeoylspermidine.
[0013] Use of the pharmaceutically acceptable salt of the above N1-dihydrocaffeoyl-N10-caffeoylspermidine in the preparation of an acetylcholinesterase inhibitor.
[0014] Use of the above N1-dihydrocaffeoyl-N10-caffeoylspermidine in the preparation of a drug for treating diseases related to abnormal elevation of acetylcholinesterase.
[0015] Use of the pharmaceutically acceptable salt of the above N1-dihydrocaffeoyl-N10-caffeoylspermidine in the preparation of a drug for treating diseases related to abnormal elevation of acetylcholinesterase.
[0016] The diseases related to abnormal elevation of acetylcholinesterase are Alzheimer's disease, myasthenia gravis or glaucoma.
[0017] Advantages of the present invention: By using in vitro enzyme activity test experiments, it is first discovered that N1-dihydrocaffeoyl-N10-caffeoylspermidine has acetylcholinesterase inhibitory activity and can be used for the treatment of diseases with abnormal elevation of acetylcholinesterase, providing a new use for N1-dihydrocaffeoyl-N10-caffeoylspermidine. Description of the drawings
[0018] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only the embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained according to the provided drawings.
[0019] Figure 1 It is the chemical structure diagram of N1-dihydrocaffeoyl-N10-caffeoylspermidine.
[0020] Figure 2 It is the graph of the half-inhibitory concentration IC of N1-dihydrocaffeoyl-N10-caffeoylspermidine against acetylcholinesterase 50 Test result graph. Detailed implementation manners
[0021] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.
[0022] In the following examples, N1-dihydrocaffeoyl-N10-caffeoylspermidine used is the compound shown in the above formula (1), which can be obtained by commercial purchase or experimental self-preparation.
[0023] The medicaments required for the present invention are conventional experimental medicaments, purchased from commercial channels; the experimental methods not mentioned are conventional experimental methods, which will not be elaborated here one by one. Example 1
[0024] Inhibitory effect of N1-dihydrocaffeoyl-N10-caffeoylspermidine on acetylcholinesterase (IC 50 ). Prepare a series of N1-dihydrocaffeoyl-N10-caffeoylspermidine sample solutions with concentrations of 5 μg / mL, 10 μg / mL, 15 μg / mL, 20 μg / mL, 25 μg / mL, 30 μg / mL, 35 μg / mL, 40 μg / mL, 50 μg / mL, 60 μg / mL, 100 μg / mL, and 200 μg / mL respectively. Take 200 μL of each and add 400 μL of acetylcholinesterase solution with a concentration of 1 mg / mL. After mixing, react at 37 °C for 30 minutes. Then add 400 μL of acetylcholine solution with a concentration of 500 μg / mL respectively, and react for 30 minutes after mixing. Subsequently, add 200 μL of choline oxidase at 50 μg / mL, 400 μL of 3,3',5,5'-tetramethylbenzidine at 1 mg / mL, and 200 μL of horseradish peroxidase at 5 μg / mL. After reacting for 30 minutes, add 200 μL of 3,3',5,5'-tetramethylbenzidine color development termination solution. Finally, measure the absorbance values of each solution at a wavelength of 450 nm, and calculate the IC of N1-dihydrocaffeoyl-N10-caffeoylspermidine inhibiting acetylcholinesterase 50 value, and the results are shown in Figure 2 As shown. The results show that the IC of N1-dihydrocaffeoyl-N10-caffeoylspermidine 50The value is 87.1 μM. The above indicates that N1-dihydrocaffeoyl-N10-caffeoylspermidine has a good effect on inhibiting acetylcholinesterase activity. Therefore, N1-dihydrocaffeoyl-N10-caffeoylspermidine can be used to prepare drugs for treating diseases with abnormally elevated acetylcholinesterase, and the diseases related to abnormally elevated acetylcholinesterase are Alzheimer's disease, myasthenia gravis or glaucoma.
[0025] As mentioned above, it is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and all should be covered within the protection scope of the present invention.
Claims
1. Use of N1-dihydrocaffeoyl-N10-caffeoylspermidine in the preparation of an acetylcholinesterase inhibitor, characterized in that, The structure of N1-dihydrocaffeoyl-N10-caffeoylspermidine is shown in formula (1): Formula (1).
2. The application according to claim 1, wherein The inhibitor also includes a pharmaceutically acceptable salt of N1-dihydrocaffeoyl-N10-caffeoylspermidine.
3. The application according to claim 1, characterized in that, Use of N1-dihydrocaffeoyl-N10-caffeoylspermidine having acetylcholinesterase inhibitory activity in the preparation of a medicament for treating diseases associated with abnormally elevated acetylcholinesterase.
4. The use according to claim 3, characterized in that, The diseases associated with abnormally elevated acetylcholinesterase are Alzheimer's disease, myasthenia gravis or glaucoma.
5. The pharmaceutically acceptable salt according to claim 2, wherein, Use of a pharmaceutically acceptable salt of N1-dihydrocaffeoyl-N10-caffeoylspermidine having acetylcholinesterase inhibitory activity in the preparation of a medicament for treating diseases associated with abnormally elevated acetylcholinesterase.
6. The use according to claim 5, characterized in that, The diseases associated with abnormally elevated acetylcholinesterase are Alzheimer's disease, myasthenia gravis or glaucoma.