Drug for treating or preventing methamphetamine addiction, and use

Abstract

Disclosed in the present invention are a drug for treating or preventing methamphetamine addiction, and the use. Also disclosed is a new use of an ERK inhibitor. In the present invention, the use of an ERK inhibitor in drug addiction is studied. The inhibitory effect of GDC-0994 in the treatment of methamphetamine addiction is studied by means of methamphetamine addiction models (including a place preference model and a self-administration experiment model), and it is found that the administration of the ERK inhibitor GDC-0994 can significantly reduce the seeking and ingesting of methamphetamine in animals, that is, the ERK inhibitor GDC-0994 can antagonize methamphetamine addiction, this indicates that the inhibition of ERK by GDC-0994 can effectively treat methamphetamine addiction.

Description

A medicine for treating or preventing methamphetamine addiction and its application Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a drug for treating or preventing methamphetamine addiction and its application. Background Art

[0002] Methamphetamine (METH), also known as methamphetamine and methylamphetamine, is one of the most widely used psychoactive substances and the most abused synthetic drug in my country. Its most common solid form, methamphetamine hydrochloride, is a colorless, transparent crystal that resembles ice, hence its nickname, "ice." Small doses can produce euphoria, alertness, talkativeness, high spirits, active thinking, and elevated moods, allowing for long periods of work or study without fatigue or hunger. Long-term abuse can lead to chronic poisoning, weight loss, emaciation, ulcers, abscesses, brittle nails, and nocturnal teeth grinding. Intravenous abuse can lead to various infectious complications, including hepatitis, bacterial endometritis, sepsis, and HIV. Severe cases can develop mental confusion, hypersexuality, anxiety, irritability, and hallucinations. Initial suspicion and sensitivity can progress to paranoid ideas or delusions, accompanied by corresponding mood swings. Driven by delusions, abusers can engage in impulsive and even violent behavior, including suicide or homicidal behavior. Overdose of methamphetamine can lead to acute poisoning or even death. Methamphetamine abuse is extremely harmful, yet there is a lack of effective treatment.

[0003] ERK, or Extracellular Signal-Regulated Kinases, is a serine / threonine protein kinase found extensively in the cytoplasm and a key component of the MAPK (mitogen-activated protein kinase) signal transduction system. ERK has important physiological functions, participating in multiple processes including cell survival, proliferation, apoptosis, immunity, metabolism, synaptic plasticity, and tumorigenesis. In the field of drug addiction, ERK may be involved in drug reward, withdrawal, and relapse, but there are currently no confirmed reports that inhibiting ERK can alleviate methamphetamine addiction.

[0004] GDC-0994 is a small molecule inhibitor of ERK that effectively inhibits ERK activity and ERK phosphorylation. Currently, GDC-0994 is primarily used in anti-tumor applications and has not been reported in drug addiction.

[0005] Therefore, the existing technology still needs to be improved and developed.

[0006] Summary of the Invention

[0007] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a drug and application for treating or preventing methamphetamine addiction, aiming to solve the problem of the lack of effective drugs for treating methamphetamine addiction.

[0008] The first aspect of the present invention provides the use of an ERK inhibitor in the preparation of a drug for treating or preventing methamphetamine addiction.

[0009] Optionally, the ERK inhibitor is GDC-0994, and the chemical structural formula of GDC-0994 is:

[0010] A second aspect of the present invention provides a drug for treating or preventing methamphetamine addiction, wherein the main component of the drug is an ERK inhibitor.

[0011] Optionally, the ERK inhibitor is GDC-0994.

[0012] Preferably, the effective dose of GDC-0994 for intracranial administration is 1 μmol.

[0013] Optionally, the drug is a drug prepared with an effective dose of GDC-0994 as the main ingredient and pharmaceutically acceptable excipients or auxiliary ingredients.

[0014] Optionally, the dosage form of the drug is one of a solution, a mixture, and an injection.

[0015] Beneficial Effects: The present invention provides the use of an ERK inhibitor in the preparation of a drug for treating or preventing methamphetamine addiction. Through experiments on a methamphetamine addiction model, the present invention found that administration of the ERK inhibitor GDC-0994 significantly reduced methamphetamine-induced conditioned place preference (CPP) values ​​and the animals' seeking and intake of methamphetamine. This indicates that the ERK inhibitor GDC-0994 can antagonize methamphetamine-induced addictive behaviors, suggesting that GDC-0994's ERK inhibition is an effective treatment for methamphetamine addiction. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 shows that administration of GDC-0994 reduced METH-induced place preference in mice. t-test, *P < 0.05.

[0017] Figure 2 shows that GDC-0994 administration reduces METH-induced self-administration in mice. Figure 2 (A) shows the number of active nose touches per two hours after GDC-0994 injection; (B) shows the amount of active food intake per two hours after GDC-0994 injection; and (C) shows the number of inactive nose touches per two hours after GDC-0994 injection. Two-way ANOVA, *P < 0.05. DETAILED DESCRIPTION

[0018] The present invention provides a drug and application for treating or preventing methamphetamine addiction. To make the objectives, technical solutions, and effects of the present invention clearer and more specific, the present invention is described in further detail below. It should be understood that the specific embodiments described herein are merely illustrative of the present invention and are not intended to limit the present invention.

[0019] GDC-0994 is a small molecule inhibitor of ERK that can effectively inhibit the activity and phosphorylation of ERK. Currently, GDC-0994 is mainly used in anti-tumor applications and has not been reported in drug addiction. In the field of drug addiction, changes in synaptic plasticity are an important molecular basis, and ERK plays an important role in synaptic plasticity. Therefore, the inventors first proposed a hypothesis: using the ERK small molecule inhibitor GDC-0994 to reduce the rewarding effect of addictive drugs and treat methamphetamine addiction. GDC-0994 is an effective selective ERK1 / 2 inhibitor with acceptable safety. In the present invention, the above hypothesis was further confirmed using the mouse place preference model (conditioned place preference, CPP) and the self-administration model (self-administration, SA). Preliminary research results suggest that GDC-0994 can be used as a candidate drug for treating methamphetamine addiction in patients.

[0020] Based on this, an embodiment of the present invention provides the use of an ERK inhibitor in the preparation of a drug for treating or preventing methamphetamine addiction.

[0021] In one embodiment, the ERK inhibitor is GDC-0994, and the chemical structure of GDC-0994 is:

[0022] The ERK inhibitor GDC-0994 can significantly reduce the CPP value induced by methamphetamine and the animals' seeking and intake of methamphetamine, that is, the ERK inhibitor GDC-0994 can antagonize the addictive behavior of methamphetamine, thereby effectively treating methamphetamine addiction.

[0023] An embodiment of the present invention provides a drug for treating or preventing methamphetamine addiction, wherein the main component of the drug is an ERK inhibitor.

[0024] In one embodiment, the ERK inhibitor is GDC-0994.

[0025] In one embodiment, the effective dose of GDC-0994 is 1 μmol.

[0026] In one embodiment, the drug is a drug prepared by using an effective dose of GDC-0994 as a main component and adding pharmaceutically acceptable excipients or auxiliary ingredients.

[0027] In one embodiment, the dosage form of the drug includes but is not limited to solution, mixture, injection and other dosage forms.

[0028] The present invention is further illustrated below by means of specific examples. The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0029] Example 1

[0030] 1. Prepare appropriate concentration of GDC-0994

[0031] (1) Prepare the stock solution: Add 5 mg of GDC-0994 powder to 2.73 mL of dimethyl sulfoxide (DMSO) and mix well to prepare a stock solution with a GDC-0994 concentration of 5 mM. Aliquot and store at -80°C for long-term storage.

[0032] (2) Prepare the application solution (prepared immediately before use): dilute the prepared stock solution 5000 times to obtain an application solution with a GDC-0994 concentration of 1 μmol, as follows: add 1 μL of the stock solution to 15 μL of PEG300 (polyethylene glycol with a molecular weight of 300) and mix well; then add 4 μL of Tween-80 (sorbitan monooleate polyoxyethylene ether) to the above system, mix well, and then add 4.98 mL of normal saline to obtain the application solution.

[0033] 2. Efficacy study of intracranial administration of GDC-0994

[0034] (1) Experimental animals

[0035] Six-week-old wild-type C57 / BL6J mice were selected and allowed free access to food during the experiment. After two weeks of feeding, intracranial catheterization was performed, followed by five days of postoperative rest.

[0036] (2) Experimental methods

[0037] a. Place preference experiment

[0038] Twelve mice were randomly divided into two groups of six: a control group (solvent) and a GDC-0994 treatment group. On the first day of the experiment, the mice were placed in a conditioned place box consisting of two connected compartments for acclimation. On the second day, the mice were placed in the conditioned place box for 15 minutes, and the time spent in each compartment was recorded. The side in which the mice spent more time was defined as the preferred compartment, and the other as the non-preferred compartment. The mice were tested once on the third day, and the average of the tests on the second and third days was used as the baseline preference. During training, the left and right compartments of the box were blocked. Every morning, mice were given an intraperitoneal injection of methamphetamine (1.5 mg / kg) and immediately placed in the non-preferred compartment (this compartment served as the companion drug compartment). Every afternoon, mice were given an intraperitoneal injection of saline and then placed in the preferred compartment. Every morning, before training, the experimental group received an intracranial injection of GDC-0994 (the prepared application solution), while the control group received an intracranial injection of the solvent (saline). Training sessions lasted 40 minutes after each administration of methamphetamine or saline, and continued for six consecutive days. On the tenth day, the partitions between the compartments were removed, allowing the mice to move freely between them. The mice were then tested for 15 minutes to determine how long they remained in each compartment. The CPP value was calculated by dividing the time spent in the drug box after training by the time spent in the drug box before training. Through training, due to the rewarding effects of methamphetamine, the mice developed a preference for the drug box, as evidenced by a significant increase in CPP. If the treatment is effective and reduces the addictive properties of methamphetamine, the mice's preference for the drug box will decrease.

[0039] b. Self-administration experiment

[0040] To acquire self-administration behavior, mice were surgically cannulated with a silicone tube inserted and secured into their jugular veins. After a week of postoperative recovery, the animals were placed in a self-administration box for self-administration training. In the box, a nose-poke hole (active poke hole) on one side of the box was coupled to an intravenous infusion of METH (0.05 mg / kg / infusion) accompanied by light and sound cues. This hole allowed the mice to receive a single methamphetamine injection. However, after receiving this injection, there was a 20-second refractory period, during which the mice could not obtain the drug even if they nose-poke the hole. A second nose-poke hole was required 20 seconds later to obtain the drug. The other side of the box (inactive poke hole) was not coupled to any event, meaning that mice could not obtain methamphetamine by nose-poke. Before the experiment, the experimental group received an intracranial injection of GDC-0994, while the control group received a vehicle (artificial cerebrospinal fluid or saline). Training was conducted for 2 hours daily for 10 consecutive days. Due to the addictive nature of METH, mice will touch the effective nasal contact hole more often to take in more drugs; if the therapeutic drug is effective, it will reduce the number of effective nasal contacts and drug pumping times induced by METH.

[0041] The experimental results are shown in Figures 1 and 2. Figure 1 shows that GDC-0994 administration reduced METH-induced place preference in mice. t-test, *P<0.05. Figure 2 shows that GDC-0994 administration reduced METH-induced self-administration in mice. In Figure 2, A represents the number of active nose-touches per two hours after GDC-0994 injection; B represents the active intake per two hours after GDC-0994 injection; and C represents the number of inactive nose-touches per two hours after GDC-0994 injection. Two-way ANOVA, *P<0.05. These results demonstrate that, in a methamphetamine addiction model, ERK inhibition using the small molecule compound GDC-0994 significantly reduced methamphetamine-induced CPP and self-administration behavior. This indicates that ERK inhibition significantly reduces methamphetamine-induced addiction in a classic behavioral paradigm, suggesting that ERK inhibition is an effective treatment for methamphetamine addiction.

[0042] It should be understood that the application of the present invention is not limited to the above examples. For those skilled in the art, improvements or changes can be made based on the above description. All these improvements and changes should fall within the scope of protection of the claims attached to the present invention.

Claims

1. Use of an ERK inhibitor in the preparation of a drug for treating or preventing methamphetamine addiction.

2. Use of the ERK inhibitor according to claim 1 in the preparation of a drug for treating methamphetamine addiction, characterized in that The ERK inhibitor is GDC-0994, and the chemical structural formula of GDC-0994 is as follows:

3. A drug for treating or preventing methamphetamine addiction, characterized in that The main component of the drug is an ERK inhibitor.

4. The drug for treating or preventing methamphetamine addiction according to claim 3, characterized in that The ERK inhibitor is GDC-0994, and the chemical structural formula of GDC-0994 is:

5. The drug for treating or preventing methamphetamine addiction according to claim 4, characterized in that The effective dose of the GDC-0994 is 1 μmol.

6. The drug for treating or preventing methamphetamine addiction according to claim 3, characterized in that The drug is prepared from the GDC-0994 as the main component in an effective dose, plus pharmaceutically acceptable excipients or auxiliary components.

7. The drug for treating or preventing methamphetamine addiction according to claim 3, characterized in that The dosage form of the drug is one of solution, mixture, and injection.

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