Application of (1, 2, 3-trimethoxybenzene)-propenone as TrkB agonist in preparation of medicine for preventing or treating TrkB disorder related brain injury

Abstract

The invention relates to application of (1, 2, 3-trimethoxybenzene)-propenone as a TrkB agonist in preparation of drugs for prevention or treatment of TrkB disorder-related brain injury, the (1, 2, 3-trimethoxybenzene)-propenone as a specific ligand of TrkB selectively binds to an extracellular domain of a TrkB protein, the affinity is significantly higher than that of a known ligand, the TrkB protein and a downstream signal channel thereof are activated, and the TrkB disorder-related brain injury is inhibited. The effect of the TrkB agonist is exerted to improve and protect the nervous system; the (1, 2, 3-trimethoxybenzene)-propenone is used as an artificially designed and synthesized small molecule drug, and is the artificially designed and synthesized TrkB small molecule agonist found for the first time, and the innovative achievement not only broadens the research and development thought of the existing TrkB agonist, but also improves the research and development efficiency of the TrkB agonist. And a new direction is provided for solving the clinical requirements which are not met in the current nervous system disease treatment field, and great breakthrough of neurodegenerative disease and brain injury treatment strategies is expected to be promoted.

Description

Technical Field

[0001] The present invention relates to the fields of biology and medicine, and particularly to the use of (1,2,3-trimethoxyphenyl)-propenone as a TrkB agonist in the preparation of a drug for preventing or treating brain damage associated with TrkB (neurotrophic factor receptor tyrosine kinase B) disorder. Background Art

[0002] TrkB (neurotrophin receptor tyrosine kinase B) is closely associated with a variety of neurological diseases. In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), dysfunction in the TrkB signaling pathway leads to abnormal regulation of neuronal survival, maturation, and function, exacerbating disease progression. For example, TrkB expression is reduced in the hippocampus of AD patients, impairing long-term potentiation (LTP) and synaptic plasticity, and inducing cognitive impairment. In psychiatric disorders, TrkB dysfunction in the brains of patients with depression and schizophrenia affects hippocampal neurogenesis and glutamatergic synaptic transmission, thereby interfering with neuroplasticity and mood regulation. Animal experiments have shown that regulating TrkB signaling can improve depressive-like behavior and schizophrenia symptoms. In addition, in neurological diseases such as ischemic stroke and spinal cord injury, TrkB plays a dual role by regulating inflammation, apoptosis, and neural repair mechanisms: during cerebral ischemia, the truncated TrkB-T1 promotes neuronal damage, while activation of the full-length TrkB-FL protects neuronal function. Therapeutic strategies targeting TrkB have become a hot topic in neurological disease research, but technical difficulties such as its receptor subtype specificity and blood-brain barrier penetration still need to be further explored.

[0003] Due to its superior performance and safety, (1,2,3-trimethoxyphenyl)-propenone has been reported in current research for its use in improving age-related macular degeneration and glutamate-induced neurotoxicity. Patent Publication No. CN109528697 discloses the use of (1,2,3-trimethoxyphenyl)-propenone in the preparation of a drug for ameliorating glutamate-induced neurotoxicity, and Patent Publication No. CN109620819 discloses the use of (1,2,3-trimethoxyphenyl)-propenone in the preparation of a drug for ameliorating age-related macular degeneration. Patent Application No. 202410716058.X discloses the use of (1,2,3-trimethoxyphenyl)-propenone in regulating brain and liver function damage caused by sleep disorders and circadian rhythm disorders. Currently, there is no research on the target of (1,2,3-trimethoxyphenyl)-propenone. Summary of the Invention

[0004] The present invention aims to provide the use of (1,2,3-trimethoxyphenyl)-propenone as a TrkB agonist in the preparation of a medicament for preventing or treating brain damage associated with TrkB disorder. The invention demonstrates that (1,2,3-trimethoxyphenyl)-propenone is a TrkB selective agonist suitable for neuroprotection of disorders and conditions associated with TrkB disorder, including but not limited to central nervous system damage diseases associated with BDNF / TrkB signaling pathway disorders.

[0005] In order to achieve the above objects, the technical solution of the present invention is:

[0006] Use of (1,2,3-trimethoxyphenyl)-propenone as a TrkB agonist in the preparation of a drug for preventing or treating brain damage associated with TrkB disorder,

[0007] The molecular formula of (1,2,3-trimethoxybenzene)-propylene ketone is C21H24O7, and the relative molecular weight is

[0008]

[0009] The weight is 388.43, and its structural formula is as follows:

[0010] The TrkB agonist can activate the brain-derived neurotrophic factor (BDNF) receptor tropomyosin receptor kinase B (TrkB), activate the expression of BDNF signaling pathway proteins, upregulate the expression and utilization of TrkB, or upregulate the expression or utilization of genes related to TrkB-mediated BDNF signaling in cells or organisms.

[0011] The (1,2,3-trimethoxyphenyl)-propenone acts as a TrkB protein ligand, selectively binds to the extracellular segment of the TrkB protein, activates the TrkB protein and its downstream signaling pathway, and exerts the efficacy of a TrkB agonist to improve or protect the nervous system.

[0012] The TrkB dysregulation refers to a condition caused or exacerbated by the inhibition of BDNF signaling or any other intracellular signaling activated by TrkB.

[0013] The drug for preventing or treating brain damage associated with TrkB disorder comprises a drug compound having the chemical formula of (1,2,3-trimethoxyphenyl)-propenone or a pharmaceutically acceptable salt thereof.

[0014] The drug for preventing or treating brain damage associated with TrkB disorder is a pharmaceutical composition of (1,2,3-trimethoxyphenyl)-propenone and an excipient, wherein the excipient is selected from any one of coatings, adhesives, salts, anti-adhesives, diluents and fillers.

[0015] The drug for preventing or treating brain damage associated with TrkB disorder includes tablets, capsules, or injections.

[0016] The drug for preventing or treating brain damage related to TrkB disorder comprises a pharmaceutical composition consisting of (1,2,3-trimethoxyphenyl)-propenone and other therapeutic agents.

[0017] The drug for preventing or treating brain damage associated with TrkB disorder also includes (1,2,3-trimethoxybenzene)-propenone derivatives, or pharmaceutical compositions composed of (1,2,3-trimethoxybenzene)-propenone derivatives and other therapeutic agents.

[0018] The beneficial effects of the present invention are:

[0019] 1. The present invention confirms for the first time that (1,2,3-trimethoxyphenyl)-propenone can specifically bind to tropomyosin receptor kinase B (TrkB) and precisely regulate the TrkB signaling pathway as a selective activator. This discovery has significant medical significance because damage to the TrkB signaling pathway is closely related to the pathological mechanisms of various neurodegenerative diseases and brain damage. The compounds of the present invention can effectively restore the activity of damaged neurons and promote the plasticity repair of synapses by enhancing the signal transduction efficiency of TrkB receptors, thereby providing a new molecular intervention strategy for the treatment of various brain injury-related diseases including ischemic stroke, traumatic brain injury, and Alzheimer's disease.

[0020] 2. Through precise measurements using surface plasmon resonance (SPR) technology, we found that the binding constant of (1,2,3-trimethoxyphenyl)-propenone to TrkB is 890nM, indicating that it can more efficiently occupy and activate the TrkB receptor under physiological conditions. This significant binding advantage not only improves the drug's pharmacodynamic potential, but also lays a solid structural foundation for the development of new nervous system drugs with a higher therapeutic index.

[0021] In summary, (1,2,3-trimethoxyphenyl)-propenone, as an artificially designed small molecule drug, is the first artificially designed small molecule TrkB agonist discovered. This innovative achievement not only broadens the existing research and development ideas of TrkB agonists, but also provides a new direction for addressing the unmet clinical needs in the current treatment of neurological diseases, and is expected to promote major breakthroughs in the treatment strategies of neurodegenerative diseases and brain injuries. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 (a) is the fitting diagram of the binding experiment between (1,2,3-trimethoxyphenyl)-propenone and TrkA, where Figure 1(b) is the sensorgram of the binding experiment between 1,2,3-trimethoxyphenyl)-propenone and TrkA. Figure 1 (c) is the fitting diagram of the binding experiment between (1,2,3-trimethoxyphenyl)-propenone and TrkB. Figure 1 (d) is the sensorgram of the binding experiment between (1,2,3-trimethoxyphenyl)-propenone and TrkB. Figure 1 (e) is the fitting diagram of the binding experiment between (1,2,3-trimethoxyphenyl)-propenone and TrkC. Figure 1 (f) in the figure is the sensorgram of the binding experiment of (1,2,3-trimethoxyphenyl)-propenone and TrkC.

[0023] Figure 2 This is a graph showing the results of detecting the protein expression level of (1,2,3-trimethoxyphenyl)-propenone in the SH-SY5Y cell line by activating TrkB phosphorylation in a time-dependent manner.

[0024] Figure 3 This is the result of the neuroprotective experiment of (1,2,3-trimethoxyphenyl)-propenone in an animal model of brain damage, where: Figure 3 (a) is the total movement distance in the open field experiment. Figure 3 (b) is the number of times the open field experiment enters the central area. Figure 3 (c) is the number of times the open field test enters the peripheral area. Figure 3 (d) Proportion of entries into the open arm in the elevated cross experiment.

[0025] Figure 4 This is a graph showing the results of detecting the effect of (1,2,3-trimethoxyphenyl)-propenone on the expression level of BDNF / TrkB signaling pathway proteins in the cerebral cortex of animals with brain function damage. DETAILED DESCRIPTION

[0026] The present invention will be further described below with reference to specific embodiments and the accompanying drawings. However, it should be understood that the protection scope of the present invention is not limited by the specific embodiments.

[0027] Example 1

[0028] (1,2,3-Trimethoxyphenyl)-propenone acts as a ligand for TrkB protein and selectively binds to the extracellular domain of TrkB protein.

[0029] In the SPR experiment, TrkB (TargetMol, USA, TMAY-00751) was functionalized by immobilizing it on the surface of a CM5 (Cytiva, USA) sensor chip. (1,2,3-Trimethoxyphenyl)-propenone in a PBS-P solution (Cytiva) was injected onto the chip. The analyte was measured using five dilutions, injected at a flow rate of 30 μL / min for 120 seconds, followed by a 150-second dissociation period. SPR detects changes in the refractive index caused by molecular binding near the chip surface, expressed as response units (RU). The association and dissociation phases are monitored to create a sensorgram, and data analysis reveals the kinetic constant between the small molecule and the protein - kd (affinity).

[0030] Reference Figure 1 The binding affinity of (1,2,3-trimethoxyphenyl)-propenone to the extracellular segment of TrkB protein was 1.726E-10, while it could not bind to TrkA and TrkC, indicating that (1,2,3-trimethoxyphenyl)-propenone can serve as a selective agonist of TrkB protein.

[0031] Example 2

[0032] (1,2,3-Trimethoxyphenyl)-propenone activates TrkB protein and its downstream signaling pathway

[0033] SH-SY5Y cell lines were cultured in F12 / DMEM supplemented with 10% fetal bovine serum and 1% penicillin and streptomycin. Cells were plated at appropriate density in 6-well plates. When the cells grew to 80% density, 0.5 μM TAK was added and treated for 0, 5, 15, 30, 60, and 120 minutes, respectively. Samples were collected and the phosphorylation activation of TrkB protein was detected.

[0034] Reference Figure 2 , (1,2,3-Trimethoxyphenyl)-propenone can activate the phosphorylation level of TrkB protein in a time-dependent manner.

[0035] Example 3

[0036] Application of (1,2,3-trimethoxyphenyl)-propenone as a TrkB selective agonist in the preparation of drugs for preventing or treating brain damage associated with TrkB disorder

[0037] Reference Figure 3 and Figure 4 A rat brain function injury model was established by the small platform water environment sleep deprivation method, and 50 mg / kg (1,2,3-trimethoxyphenyl)-propenone was administered by oral gavage for protection. The behavioral phenotype of rat brain injury was detected by the open field test and the elevated cross test, and the background of the BDNF / TrkB signaling pathway and its phosphorylated protein expression level in the rat cortex were detected.

[0038] Subjects with impending or developing TrkB receptor activation-related conditions, including neurological and psychiatric disorders, specifically sleep disorders, depression, mania, Alzheimer's disease, central nervous system damage, and other conditions associated with BDNF / TrkB signaling pathway dysregulation, were selected. A therapeutically effective dose of a modified (1,2,3-trimethoxyphenyl)-propenone agent, or a combination therapy, was administered systemically or topically. The effective adult ingestion concentration range was 8 mg per kilogram of body weight per day. (The rat-to-human dose conversion ratio was 1:0.16.)

[0039] For the first time, it was discovered that the compound (1,2,3-trimethoxybenzene)-propenone specifically binds to the TrkB protein, can activate TrkB activity and exert neuroprotective function, and can be used to prepare drugs to alleviate the occurrence and development of central nervous system diseases related to BDNF / TrkB disorders.

[0040] Explanation of terms

[0041] The term "neuroprotection" means that the TrkB agonists disclosed herein can maintain normal neuronal structure and function compared to untreated cells or organisms resulting from impairment of neuronal structure or function in the nervous system.

[0042] The term "derivative" refers to any compound that is a chemically or biologically altered form of a chemical compound that is structurally similar to the parent compound or derived from the parent compound. A derivative may or may not possess the physical or chemical properties of the parent compound. A derivative may have significantly greater affinity or reactivity than the parent compound. Derivatives also refer to modifications resulting from the substitution of one or more moieties within the molecule. Derivatives also include conjugates and prodrugs of the parent compound—chemically modified derivatives that can be converted to the original compound under physiological conditions.

[0043] The term "pharmaceutical composition" refers to a mixture of one or more other chemical components of the compound or a pharmaceutically acceptable salt thereof, and a physically acceptable carrier or excipient, often in the form of tablets, capsules, pills or injections. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

[0044] The term "excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration. Examples of excipients include, but are not limited to, starch, gelatin, sugars, and the like.

[0045] The terms "including, such as, for example" and the like are intended to indicate exemplary aspects and are not intended to limit the scope of the disclosure.

Claims

1. Use of (1,2,3-trimethoxyphenyl)-propenone as a TrkB agonist in the preparation of a drug for preventing or treating brain damage associated with TrkB disorder, characterized in that: The molecular formula of the (1,2,3-trimethoxybenzene)-propylene ketone is C21 H24O7, the relative molecular weight is 388.43, and its structural formula is as follows:

2. The use according to claim 1, characterized in that The TrkB agonist can activate the brain-derived neurotrophic factor (BDNF) receptor tropomyosin receptor kinase B (TrkB), activate the expression of BDNF signaling pathway proteins, upregulate the expression and utilization of TrkB, or upregulate the expression or utilization of genes related to TrkB-mediated BDNF signaling in cells or organisms.

3. The use according to claim 1, characterized in that The (1,2,3-trimethoxyphenyl)-propenone acts as a TrkB protein ligand, selectively binds to the extracellular segment of the TrkB protein, activates the TrkB protein and its downstream signaling pathway, and exerts the efficacy of a TrkB agonist to improve or protect the nervous system.

4. The use according to claim 1, characterized in that The TrkB dysregulation refers to a condition caused or exacerbated by the inhibition of BDNF signaling or any other intracellular signaling activated by TrkB.

5. The use according to claim 1, characterized in that The drug for preventing or treating brain damage associated with TrkB disorder comprises a drug compound having the chemical formula of (1,2,3-trimethoxyphenyl)-propenone or a pharmaceutically acceptable salt thereof.

6. The use according to claim 1, characterized in that The drug for preventing or treating brain damage associated with TrkB disorder is a pharmaceutical composition of (1,2,3-trimethoxyphenyl)-propenone and an excipient, wherein the excipient is selected from any one of coatings, adhesives, salts, anti-adhesives, diluents and fillers.

7. The use according to claim 1, characterized in that The drug for preventing or treating brain damage associated with TrkB disorder includes tablets, capsules, or injections.

8. The use according to claim 1, characterized in that The drug for preventing or treating brain damage related to TrkB disorder comprises a pharmaceutical composition consisting of (1,2,3-trimethoxyphenyl)-propenone and other therapeutic agents.

9. The use according to claim 1, characterized in that The drug for preventing or treating brain damage associated with TrkB disorder also includes (1,2,3-trimethoxybenzene)-propenone derivatives, or pharmaceutical compositions composed of (1,2,3-trimethoxybenzene)-propenone derivatives and other therapeutic agents.

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