Application of N1, N10-dicaffeoyl spermidine in preparation of acetylcholin esterase inhibitor
N1,N10-dicaffeoylspermidine, a natural compound from Lycium fruit, 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
- CN202510569520.2
- 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 chemically synthesized AChE inhibitors have side effects, low bioavailability, easy to develop drug resistance and high production costs, and cannot effectively treat diseases related to abnormally elevated acetylcholinesterase.
N1,N10-dicafenylspermide was used as a natural compound. Through in vitro enzyme activity experiments, it was found that it had a significant inhibitory effect on acetylcholinesterase, and it was developed as a pharmaceutically acceptable salt for the preparation of acetylcholinesterase inhibitors.
It provides highly efficient and low-toxic AChE inhibitors, reduces side effects, improves bioavailability, and reduces production costs. It is suitable for the treatment of diseases such as Alzheimer's disease, myasthenia gravis and glaucoma.
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Figure CN120305238A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of medicinal chemistry, and particularly relates to the use of N1,N10-dicaffeoyl spermidine in the preparation of acetylcholinesterase inhibitors. Background Art
[0002] Acetylcholinesterase (AChE) is a key hydrolytic enzyme that regulates the level of acetylcholine (ACh) in the central and peripheral nervous systems. It terminates the signal transmission of neurotransmitters to the postsynaptic membrane by catalyzing the decomposition of ACh into choline and acetic acid. Abnormal AChE activity is closely related to various diseases, including neurodegenerative diseases and neuromuscular diseases. In neurodegenerative diseases such as Alzheimer's Disease (AD), abnormal elevation of AChE activity leads to a significant decrease in ACh levels, which in turn triggers pathological features such as cognitive impairment and memory decline. Therefore, inhibiting AChE activity to increase the concentration of ACh in the synaptic cleft has become an important therapeutic strategy for improving the symptoms of such diseases. Myasthenia gravis is one of the common neuromuscular diseases. AChE inhibitors (such as neostigmine) can enhance the signal transmission at the neuromuscular junction and relieve the symptoms of myasthenia. AChE inhibitors are also used in the treatment of glaucoma (by regulating intraocular pressure), anesthesia recovery (reversing the action of muscle relaxants), and the detoxification of anticholinergic drug poisoning.
[0003] Currently, the AChE inhibitors used clinically are mainly chemically synthesized drugs, such as donepezil, galantamine, and rivastigmine. Although these drugs can temporarily relieve symptoms by reversibly inhibiting AChE activity, their long-term use has obvious limitations: on the one hand, chemically synthesized inhibitors are prone to side effects such as gastrointestinal reactions and bradycardia; on the other hand, they have low bioavailability, are prone to drug resistance, and cannot reverse the disease process. In addition, the complex structures and synthesis processes of chemically synthesized drugs also increase the production cost and potential environmental burden.
[0004] In recent years, active monomer components derived from natural medicines have gradually become a research hotspot for novel AChE inhibitors due to their multi-target effects, low toxicity, and good biocompatibility. For example, huperzine A, as a natural alkaloid, has shown inhibitory activity and selectivity superior to some synthetic drugs; flavonoids, terpenoids, and phenolic acids have also been proven to improve nerve function through synergistic mechanisms such as antioxidation and anti-inflammation. Based on this, it is of great value to develop AChE inhibitors with clear structures, natural sources, and significant activities. N1,N10-dicaffeoyl spermidine is a spermidine derivative naturally present in Solanaceae plants such as Lycium barbarum or Lycium ruthenicum. Currently, there are few research reports on this compound, and its potential as an AChE inhibitor has not been fully explored. The present invention for the first time reveals the efficient inhibitory effect of N1,N10-dicaffeoyl spermidine on AChE, providing an experimental basis for its treatment of diseases with abnormally elevated acetylcholinesterase. Summary of the Invention
[0005] Through preliminary in vitro enzyme activity inhibition experiments, the present invention found that N1,N10-dicaffeoyl spermidine can significantly inhibit the activity of acetylcholinesterase.
[0006] Therefore, the purpose of the present invention is to provide the use of N1,N10-dicaffeoyl spermidine in the preparation of acetylcholinesterase inhibitors.
[0007] The second purpose of the present invention is to provide the use of pharmaceutically acceptable salts of N1,N10-dicaffeoyl spermidine in the preparation of acetylcholinesterase inhibitors.
[0008] The third purpose of the present invention is to provide the use of N1,N10-dicaffeoyl spermidine in the preparation of drugs for treating diseases related to abnormally elevated acetylcholinesterase.
[0009] The fourth purpose of the present invention is to provide the use of pharmaceutically acceptable salts of N1,N10-dicaffeoyl spermidine in the preparation of drugs for treating diseases related to abnormally elevated acetylcholinesterase.
[0010] To achieve the above purposes, the present invention adopts the following technical solutions: The use of N1,N10-dicaffeoyl spermidine in the preparation of acetylcholinesterase inhibitors, wherein the structure of N1,N10-dicaffeoyl spermidine is shown in formula (1): Formula (1).
[0011] N1,N10-dicaffeoyl spermidine, with the molecular formula C 25 H 31N3O6, with a molecular weight of 469.22, is fully known as (E)-3-(3,4-dihydroxyphenyl)-N-(3-((4-((E)-3-(3,4-dihydroxyphenyl)acrylamido)butyl)amino)propyl)acrylamide, abbreviated as N1,N3-bis(caffeoyl)spermidine or N1,N3-di-caffeoylspermidine.
[0012] Use of the pharmaceutically acceptable salt of N1,N10-dicaffeoylspermidine in the preparation of an acetylcholinesterase inhibitor.
[0013] Use of the above-mentioned N1,N10-dicaffeoylspermidine in the preparation of a medicament for treating diseases related to abnormally elevated acetylcholinesterase.
[0014] Use of the pharmaceutically acceptable salt of the above-mentioned N1,N10-dicaffeoylspermidine in the preparation of a medicament for treating diseases related to abnormally elevated acetylcholinesterase.
[0015] The diseases related to abnormally elevated acetylcholinesterase are Alzheimer's disease, myasthenia gravis or glaucoma.
[0016] Advantages of the present invention: By using in vitro enzyme activity test experiments, it is found for the first time that N1,N10-dicaffeoylspermidine has acetylcholinesterase inhibitory activity and can be used for the treatment of diseases with abnormally elevated acetylcholinesterase, providing a new use for N1,N10-dicaffeoylspermidine. Description of the drawings
[0017] 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 use in 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, other drawings can be obtained according to the provided drawings without creative efforts.
[0018] Figure 1 It is the chemical structure diagram of N1,N10-dicaffeoylspermidine.
[0019] Figure 2 It is the graph of the half inhibitory concentration IC of N1,N10-dicaffeoylspermidine on acetylcholinesterase 50 Test result graph. Detailed implementation manners
[0020] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with 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. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.
[0021] In the following examples, N1,N10-dicaffeoylspermidine used is the compound shown in the above formula (1), which can be obtained by commercial purchase or experimental self-preparation.
[0022] 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
[0023] Inhibitory effect of N1,N10-dicaffeoylspermidine on acetylcholinesterase (IC 50 ). Prepare a series of N1,N10-dicaffeoylspermidine 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, and detect the absorbance values of each solution at a wavelength of 450 nm, and calculate the IC of N1,N10-dicaffeoylspermidine inhibiting acetylcholinesterase 50 value, and the results are shown in Figure 2 As shown. The results show that the IC of N1,N10-dicaffeoylspermidine 50 value is 57.5 μM. The above shows that N1,N10-dicaffeoylspermidine has a good effect of inhibiting the activity of acetylcholinesterase. Therefore, N1,N10-dicaffeoylspermidine 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.
[0024] The above are only the preferred specific embodiments 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,N10-dicaffeoyl spermidine in the preparation of an acetylcholinesterase inhibitor, characterized in that, The structure of N1,N10-dicaffeoyl spermidine 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,N10-dicaffeoyl spermidine.
3. The application according to claim 1, wherein Use of N1,N10-dicaffeoyl spermidine 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,N10-dicaffeoyl spermidine 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.