WO2020233706A1

WO2020233706A1 - Drug for treating manic mental disorder and schizophrenia

Info

Publication number: WO2020233706A1
Application number: PCT/CN2020/091796
Authority: WO
Inventors: 李洪林; 王蕊; 张寿德; 赵振江; 毛宇
Original assignee: 华东理工大学
Priority date: 2019-05-22
Filing date: 2020-05-22
Publication date: 2020-11-26
Also published as: CN111973615A

Abstract

A drug for treating a manic mental disorder and schizophrenia, specifically, a guanine nucleoside as represented by formula I and a use of a derivative thereof in treating mental disorders such as a manic mental disorder and schizophrenia.

Description

Medicine for treating manic mental disorder and schizophrenia

Technical field

The invention belongs to the field of chemical medicine, and specifically relates to the application of a class of compounds in the treatment of manic mental disorders and schizophrenia.

Background technique

The Diagnostic Manual of the American Psychiatric Association defines mania as an abnormal mood, constant elevation, swelling, or irritability, abnormal and continuous increase in activity or energy during most of the week. In the long-term observation of the course of mood disorders, it is very rare that authors who have only mania or hypomania at all times, and these patients are similar to bipolar disorder with depressive episodes. Therefore, the International Classification System of Mental Illness (ICD-10) and the American Classification System (DSM-IV) have classified it as a kind of bipolar disorder.

Neurological studies have confirmed that patients with mania have abnormal central neurotransmitter metabolism and changes in the corresponding receptor functions. Lack of serotonin (5-HT) functional activity may be the basis of bipolar disorder and a quality indicator of susceptibility to bipolar disorder; reduced norepinephrine (NE) functional activity may be related to depressive episodes, norepinephrine function Increased activity may be related to manic episodes; dopamine (DA) functional activity is abnormal; γ-aminobutyric acid (GABA) is an inhibitory neurotransmitter of the central nervous system, and there may be abnormal functional activities. Because antiepileptic drugs acting on this neurotransmitter can be used as mood stabilizers, it is effective in treating mania and bipolar disorder. The second messenger is out of balance. The second messenger is an indispensable intermediary between extracellular information and intracellular effects; neuroendocrine dysfunction, mainly the function of the hypothalamus-pituitary-adrenal cortex axis and the hypothalamus-pituitary-thyroid axis Imbalance.

In summary, there is an urgent need in this field to develop a new drug capable of treating manic mental disorders, schizophrenia and other mental diseases.

Summary of the invention

The purpose of the present invention is a new drug capable of treating manic mental disorders, schizophrenia and other mental diseases.

In the first aspect of the present invention, there is provided a guanosine and its derivatives, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer or racemate thereof, Or the use of a prodrug thereof, wherein the use is one or more uses selected from the following group:

(a) For the preparation of compositions or preparations for the treatment and/or prevention of mental illness, and/or for alleviating the symptoms and/or physiological characteristics of mental illness;

(b) Use as an NMDA (N-methyl-D-aspartic acid) inhibitor; and/or

(c) Use as a 5-HT (preferably, 5-HTP) inhibitor; and the guanosine and its derivatives are shown in formula I,

among them,

R ¹ and R ² are each independently selected from: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl-C1-3 alkyl (preferably, benzyl), substituted Or unsubstituted C1-C6 alkyl formyl (C1-C6 alkyl-CO-) (preferably, C1-C3 alkyl formyl), substituted or unsubstituted C6-C10 aryl-formyl (C6 -C10 aryl-CO-) (preferably, benzoyl);

Q is unsubstituted or substituted by one or more (preferably, 1, 2, 3, 4 or 5) R groups, monosaccharides, disaccharides or trisaccharides; wherein each R is independently selected from The following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl-C1-3 alkyl, substituted or unsubstituted C1-C3 alkyl formyl, substituted or unsubstituted C6 -C10 aryl-formyl;

Unless otherwise specified, the substitution means that one or more hydrogens (preferably, 1, 2, 3 or 4 hydrogens) in the group are replaced by a substituent selected from the following group: halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl-C1-3 alkyl, C1-C3 alkyl formyl, C6-C10 aryl-formyl.

In another preferred example, the mental illness includes: mania (manic mental disorder) and/or schizophrenia.

In another preferred embodiment, the mania includes: hypomania and/or recurrent mania.

In another preferred example, the schizophrenia includes: paranoid schizophrenia, adolescent schizophrenia, catatonic schizophrenia, simple schizophrenia, undifferentiated schizophrenia, residual schizophrenia .

In another preferred embodiment, Q is selected from the following group: substituted or unsubstituted five-carbon sugar, substituted or unsubstituted six-carbon sugar.

In another preferred example, Q is a substituted or unsubstituted group selected from the following group:

In another preferred embodiment, the guanosine and its derivatives are as shown in formula II,

among them,

The definitions of R ¹ and R ² are the same as before;

R ³ , R ⁴ and R ⁵ are each independently selected from: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl-C1-3 alkyl, substituted or unsubstituted C1 -C3 alkyl formyl, substituted or unsubstituted C6-C10 aryl-formyl.

In another preferred embodiment, R ³ , R ⁴ and R ⁵ are each independently selected from: H, C1-C6 alkyl, C6-C10 aryl-C1-3 alkyl, C1-C3 alkyl formyl, C6 -C10 aryl-formyl.

In another preferred example, R ³ , R ⁴ and R ⁵ are each independently selected from: H, C1-C6 alkyl, benzyl, C1-C3 alkyl formyl, and benzoyl.

In another preferred embodiment, the guanosine and its derivatives are guanosine as shown in formula III (ie Guanosine, Guanosine, 118-00-3)

In the second aspect of the present invention, there is provided a guanosine and its derivatives, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers or racemates thereof, Or the use of a prodrug thereof, wherein the use is one or more uses selected from the following group:

(d) Preparation for the treatment and/or prevention of diseases induced by 5-HT and/or its precursors and/or for alleviation and/or alleviation of diseases induced by 5-HT and/or its precursors drug;

(e) For the preparation of drugs for the treatment and/or prevention of diseases mediated by PI3K/Akt signaling pathway and/or for alleviating and/or alleviating diseases and diseases mediated by PI3K/Akt signaling pathway;

(f) Used to activate PI3K/Akt signal pathway;

(g) For the preparation of drugs for treating and/or preventing diseases mediated by 5-HT receptors and diseases mediated by 5-HT receptors; and/or

(h) As a 5-HT receptor antagonist;

Wherein, the guanosine and its derivatives are as defined in the first aspect.

In another preferred embodiment, the precursor of 5-HT is 5-HTP.

In another preferred example, the disease induced by 5-HT and/or its precursors includes: serotonin syndrome, 5-HT syndrome, or a combination thereof.

In another preferred embodiment, the diseases mediated by 5-HT receptors include: serotonin syndrome, 5-HT syndrome, or a combination thereof.

In another preferred embodiment, the 5-HT receptor-mediated conditions include: serotonin syndrome behavior (SS behavior), head twitching, and/or wet dog-like shaking.

In another preferred embodiment, the 5-HT receptor includes: 5-HT _1A receptor, and/or 5-HT ₂ receptor.

In the third aspect of the present invention, a guanosine derivative is provided, and the guanosine derivative is shown in formula IV,

among them,

R ^a and R ^{b are} independently selected from: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl-C1-3 alkyl (preferably, benzyl), substituted or unsubstituted Substituted C1-C3 alkylformyl, substituted or unsubstituted C6-C10 aryl-formyl (preferably, benzoyl);

Z is unsubstituted or substituted by one or more (preferably, 1, 2, 3, 4 or 5) R groups, monosaccharides, disaccharides or trisaccharides; wherein each R is independently selected from The following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl-C1-3 alkyl, substituted or unsubstituted C1-C3 alkyl formyl, substituted or unsubstituted C6 -C10 aryl-formyl;

Unless otherwise specified, the substitution means that one or more hydrogens (preferably, 1, 2, 3 or 4 hydrogens) in the group are replaced by a substituent selected from the following group: halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl-C1-3 alkyl, C1-C3 alkyl formyl, C6-C10 aryl-formyl;

And, the guanosine derivative does not include a compound selected from the following group:

In another preferred embodiment, Z is a substituted group selected from the following group

Alternatively, Z is a substituted or unsubstituted group selected from the following group:

In another preferred embodiment, Z is selected from the following group: substituted or unsubstituted five-carbon sugar, substituted or unsubstituted six-carbon sugar.

In another preferred embodiment, the guanosine derivative is represented by formula V,

among them,

The definitions of R ^a and R ^b are the same as before;

R ^c , R ^d and R ^e are each independently selected from: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl-C1-3 alkyl, substituted or unsubstituted C1 -C3 alkylformyl, substituted or unsubstituted C6-C10 aryl-formyl; and R ^c , ^Rd and R ^{e are} not H at the same time.

In another preferred embodiment, R ^c , R ^d and R ^e are each independently selected from: H, C1-C6 alkyl, C6-C10 aryl-C1-3 alkyl, C1-C3 alkyl formyl, C6 -C10 aryl-formyl; and R ^c , ^Rd and R ^{e are} not H at the same time.

In another preferred embodiment, R ^c, R ^d and R ^e are each independently selected from: H, C1-C6 alkyl, benzyl, C1-C3 alkyl group a formyl group, a benzoyl group; and R ^c, R ^d and R ^e are not simultaneously H.

The fourth aspect of the present invention provides a pharmaceutical composition, wherein

The composition comprises (i) a first active ingredient, which is the guanosine derivative according to claim 6, and (ii) a pharmaceutically acceptable carrier; or

The composition includes (i1) a first active ingredient, the first active ingredient being the guanosine and its derivatives described in claim 1, (i2) a second active ingredient, and the second active ingredient The ingredients include: other drugs for treating and/or preventing mental illness, drugs for preventing and/or relieving symptoms of mental illness, NMDA inhibitors, 5-HT inhibitors, or combinations thereof, and (ii) pharmaceutically acceptable Accepted carrier.

In the fifth aspect of the present invention, there is provided a method for inhibiting NMDA receptors, which includes the steps of making the target interact with the guanosine and its derivatives as described in the first aspect, and the bird as described in the third aspect. The purine nucleoside derivative and/or the pharmaceutical composition as described in the fourth aspect are contacted, thereby inhibiting the NMDA receptor.

In another preferred embodiment, the method of inhibiting NMDA receptors is non-therapeutic in vitro.

In another preferred embodiment, the target is a cell.

In the sixth aspect of the present invention, there is provided a method for inhibiting 5-HT receptors, including the steps of: making the target and the guanosine and its derivatives as described in the first aspect as described in the third aspect Contact with the guanosine derivative and/or the pharmaceutical composition as described in the fourth aspect, thereby inhibiting the 5-HT receptor.

In another preferred embodiment, the method of inhibiting 5-HT receptor is non-therapeutic in vitro.

In another preferred embodiment, the target is a cell.

In the seventh aspect of the present invention, a method for activating the PI3K/Akt signaling pathway is provided, which includes the steps of: making the target and the guanosine and its derivatives as described in the first aspect as described in the third aspect Contact with the guanosine derivative of guanosine and/or the pharmaceutical composition as described in the fourth aspect, thereby activating the PI3K/Akt signaling pathway.

In another preferred embodiment, the method for activating the PI3K/Akt signaling pathway is non-therapeutic in vitro.

In another preferred embodiment, the target is a cell.

In the eighth aspect of the present invention, there is provided a method for treating and/or preventing and alleviating mental illness, and/or alleviating the symptoms of mental illness, comprising the steps of: administering to a subject in need a therapeutically effective amount of the one described in the first aspect The guanosine and its derivatives, the guanosine derivative as described in the third aspect and/or the pharmaceutical composition as described in the fourth aspect.

In another preferred example, the dosage is 0.5 mg/kg body weight to 40 mg/kg body weight.

In another preferred embodiment, the subject is a mammal; preferably, the subject is selected from the following group: mice, rats, or humans.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, I will not repeat them here.

Description of the drawings

Figure 1.1 shows the effect of guanosine on high spontaneous activity in a mouse model of schizophrenia caused by MK-801 (Figure 1.1A is the total distance of exercise, Figure 1.1B is the length of exercise, and Figure 1.1C is the average speed);

Figure 1.2 shows the effect of guanosine on the stereotyped behavior of a mouse model of schizophrenia induced by MK-801 (Figure 1.2A is the short-term stereotyped behavior score at each time, and 1.2B is the average stereotyped behavior score).

Figure 2 shows the effect of guanosine on 5-hydroxytryptophan (5-HTP)-induced wet dog shakes (WDS) behavior in rats with 5-HT syndrome and the strong serotonin caused by 5-HTP Syndrome (serotonin syndrome, SS) (Figure 2A is a broken line graph of the number of wet dog tremors in rats every five minutes, Figure 2B is a histogram of the number of wet dog tremors in rats within 60 minutes, and Figure 2C records 5-HT Other SS behavior scores induced by _1A , data are expressed as mean±SEM. ***Compared with the model group, P<0.001).

Figure 3 (E) shows that 5-HT did not cause a decrease in cAMP in SH-SY5Y; Figure 4 (F) shows that after pretreatment with guanosine, 5-HT caused an increase in cAMP in SH-SY5Y. Data are expressed as mean±SEM.

Figure 4 shows the expression of p-Akt/Akt in brain tissue and SH-SY5Y cells. (A) Relative expression of p-Akt/Akt in cortex treated with guanosine (5mg/kg) for 7 days. (B) The relative expression of p-Akt/Akt in SH-SY5Y cells pretreated with LY294002(LY) for 30 minutes and then guanosine for 60 minutes. (C) The relative expression of p-Akt/Akt in SH-SY5Y cells. The cells were pretreated with PTX for 12 hours, and then guanosine was added to the culture for 60 minutes. Data are expressed as mean±SEM. Compared with the control group, *P<0.05, **P<0.01 and ***P<0.001. Compared with the relative guanosine concentration group, #P<0.05, ##P<0.01 and ###P<0.001.

Detailed ways

After long-term and in-depth research, the inventors unexpectedly discovered that guanosine and its derivatives as shown in formula I have an effect on mental illnesses (for example, MK-801 (dizocilpine/dizocilpine) induced mental illness The cleavage-like model and 5-HTP (5-hydroxytryptophan) induced 5-HT syndrome) have a significant inhibitory effect. Based on this, the inventor completed the present invention.

the term

As used herein, the term "mania" refers to the main clinical manifestations of elevated emotions or irritability, accompanied by increased energy, increased speech, increased activity, and in severe cases, neuropsychiatric symptoms such as hallucinations, delusions, and nervousness. Mania is generally paroxysmal and lasts for more than a week. After each attack, it enters a remission period with a normal mental state intermittently. Most patients have a tendency to recurrent attacks. Generally, mania includes hypomania (hypomania): mania without psychotic symptoms; mania with psychotic symptoms. Recurrent mania: recurrent mania, currently hypomania; recurrent mania, currently mania without psychotic symptoms; recurrent mania, currently mania with psychotic symptoms.

As used in this article, schizophrenia is a group of severe mental illnesses of unknown etiology, mostly in young adults with slow or subacute onset, clinically often manifested as syndromes with different symptoms, involving perception, thinking, emotion, and behavior And many obstacles such as mental activity. Some patients eventually suffer from cognitive and thinking decline and mental disability, but some patients can remain cured or basically cured after treatment. In general, the clinical types of schizophrenia are: (1) Paranoid type: This is the most common type of schizophrenia, with hallucinations and delusions as the main clinical manifestations; (2) Youth type: onset in adolescence, Significant thinking, emotional and behavioral disorders are the main manifestations. The typical manifestations are loose thinking, broken thinking, and naive emotional and behavioral reactions, which may be accompanied by fragments of hallucinations and delusions; some patients may exhibit hyperactive instinctive activities, such as appetite, Increased libido, etc.; (3) tension type: the main manifestation of tension syndrome, patients can manifest as catatonic stupor, waxy flexion, stereotyped speech and behavior, and uncoordinated psychomotor excitement and impulsive behavior; (4) simple Type: This type is mainly onset in adolescence and mainly manifests as negative symptoms, such as withdrawn, withdrawn, flat or indifferent, etc.; (5) Undifferentiated type: This type has some of the characteristics of one of the above types, or has the above types Some characteristics, but it is difficult to be classified into any of the above types; (6) Residual type: This type is the stage after the acute phase of schizophrenia, mainly manifested as a change in personality or a decline in social function.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

Unless otherwise stated, the term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (ie, C1-C6 represents 1-6 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and the like.

Unless otherwise stated, the term "aryl" means a polyunsaturated (usually aromatic) hydrocarbon group, which may be a single ring or multiple rings fused together or covalently linked. Non-limiting examples of aryl groups include phenyl, naphthyl.

Unless otherwise defined, each abbreviation herein has a conventional meaning understood by those skilled in the art. For example, 5-HT refers to serotonin and 5-HTP refers to 5-hydroxytryptophan.

Guanosine and its derivatives

The present invention has discovered a drug that can prevent and/or treat manic mental disorders and schizophrenia, which can prevent and/or alleviate the symptoms of manic mental disorders and schizophrenia.

The present invention provides the use of guanosine and its derivatives such as guanosine as a medicine for preventing and/or treating manic mental disorders and schizophrenia, wherein the structure of the guanosine is as shown in formula III Shown:

The manic mental disorder described in the present invention is Mania. In the Chinese Classification and Diagnostic Criteria for Mental Disorders-Third Edition (CCMD-3), the main clinical manifestations are elevated emotions or irritability, accompanied by vigorous energy, increased speech, increased activity, and in severe cases, hallucinations, delusions, and tension symptoms And other psychosis-like symptoms. Manic episodes need to last for more than a week, usually with a paroxysmal course. After each episode, it enters an intermittent remission period with a normal mental state. Most patients have a tendency to recur.

The clinical symptoms of schizophrenia described in the present invention are complex and diverse, and may involve perception, thinking, emotion, volitional behavior, and cognitive functions. Symptoms vary greatly among individuals, even if the same patient is in different stages or stages of illness. It may also show different symptoms.

In a specific embodiment, the present invention provides a guanosine and its derivatives as shown in formula I and their use in mental illness;

Among them, the definition of each group is the same as that in the first aspect.

In a specific embodiment, R ¹ and R ² are each independently selected from: H, C1-C6 alkyl, benzyl, C1-C3 alkylformyl; Q is selected from optionally substituted monosaccharides, disaccharides, trisaccharides , Monosaccharide; preferably five-carbon sugar, six-carbon sugar.

In another specific embodiment, the guanosine and its derivatives are shown in formula II,

Wherein, R ¹ and R ² are each independently selected from: H, C1-C6 alkyl, benzyl, C1-C3 alkylformyl;

R ³ , R ⁴ and R ⁵ are each independently selected from: H, C1-C6 alkyl, benzyl, C1-C3 alkylformyl, and benzoyl.

In another preferred embodiment, the present invention also provides guanosine (guanosine, Guanosine, 118-00-3), or a pharmaceutically acceptable salt or prodrug thereof in the preparation, treatment, prevention or Use in medicine for relieving the clinical symptoms and pathophysiological characteristics of manic mental disorders, schizophrenia and other related mental diseases.

Preferably, the present invention determines that the dosage of guanosine and its derivatives such as guanosine is 0.5 mg/kg to 40 mg/kg.

The first experiment of the present invention found that guanosine and its derivatives such as guanosine have the following effects in the prevention and/or treatment of manic mental disorders and schizophrenia:

(1) Guanosine significantly reduces the spontaneous activity and stereotyped behavior of mice induced by MK-801 (70449-94-4, a drug used in the central nervous system, a non-competitive glutamate NMDA receptor antagonist).

(2) Guanosine significantly inhibits 5-HTP (56-69-9, the precursor of 5-HT) in rats' head shaking, body flattening, forefoot stepping, hind limb abduction, wet dog-like shaking, and head twitching And other behaviors.

The present invention proves for the first time that guanosine has the effect of treating MK-801-induced schizophrenia in mice and 5-HTP-induced 5-HT syndrome in rats, and can be used to prepare therapeutic drugs for manic mental disorders and schizophrenia .

Active ingredient

As used herein, the term "compound of the present invention" refers to the compound guanosine represented by formula I and its derivatives and/or the guanosine derivative represented by formula IV. The term also includes various crystalline forms, pharmaceutically acceptable salts, prodrugs, enantiomers, diastereomers or racemates of the compound of formula I or compound of formula IV.

Among them, the term "pharmaceutically acceptable salt" refers to a salt formed by the compound of the present invention and an acid or base suitable for use as a medicine. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are the salts of the compounds of this invention with acids. Acids suitable for salt formation include but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; and Amino acids such as amino acid, phenylalanine, aspartic acid and glutamic acid. Another type of preferred salt is the salt formed by the compound of the present invention with a base, such as alkali metal salt (such as sodium or potassium salt), alkaline earth metal salt (such as magnesium salt or calcium salt), ammonium salt (such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butyl Amine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine.

The term "prodrug" includes biologically active or inactive itself. When taken by a proper method, it undergoes metabolism or chemical reaction in the human body to convert it into a compound shown in Formula I or Formula IV. Compound, or a salt or solution composed of a compound represented by formula I or formula IV. The prodrugs include (but are not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone ester, sulfoxide ester, amino compound, carbamate, azo compound of the compound , Phosphoramide, glucoside, ether, acetal and other forms.

Preparation

The compounds of the present invention can be obtained commercially or prepared by referring to existing synthetic methods in the art.

Pharmaceutical composition and method of administration

Since the compound of the present invention has excellent prevention and/or treatment of manic mental disorder and schizophrenia, and/or excellent effect of inhibiting 5-HT receptors, the compound of the present invention and its various crystal forms are pharmaceutically acceptable Accepted inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredients can be used for the treatment, prevention and alleviation of mental diseases including mania and/or schizophrenia or by 5- Diseases or disorders induced by HT and/or its precursors or mediated by 5-HT receptors.

The pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount. The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per agent, more preferably, contains 10-500 mg of the compound of the present invention per agent. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid). , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers

Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectant, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.

In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

The composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, spray and inhalant. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.

The compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage when administered is a pharmaceutically effective dosage, and the daily dosage is usually 0.1 to 400 mg /kg body weight, preferably 0.5-40 mg/kg body weight. Of course, the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.

The main advantages of the present invention include:

(a) The compound of the present invention can effectively treat mania-type mental disorder and schizophrenia.

(b) The compound of the present invention can significantly inhibit the symptoms of mania mental disorder and schizophrenia.

The compounds of the present invention such as guanosine can dose-dependently reduce the number of wet dog-like tremors in rats, indicating that guanosine blocks serotonin receptors. The serotonin system contains 14 receptors, most of which are coupled to G protein. Among them, the compound of the present invention may exert an antagonistic effect on 5-HT _1A in SH-SY5Y cells. Because most SS behavioral responses are mediated by G _i/o coupled 5-HT ₁ receptors. In addition, PI3K inhibitor LY294002 and G _i/o receptor inhibitor PTX reduced the increase in Akt phosphorylation in SH-SY5Y cells. These results indicate that guanosine may activate the PTX-sensitive G _i/o coupled PI3K/Akt signal.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods that do not indicate specific conditions in the following examples usually follow the conventional conditions or the conditions suggested by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and parts by weight.

Unless otherwise specified, the reagents, buffers, etc. used in the following test examples are all commercially available or prepared according to methods known in the art.

Test Example 1: The inhibitory effect of the compound on the spontaneous activity and stereotyped behavior of mice induced by MK-801

In this experiment, ICR mice were used to establish a schizophrenia-like model induced by MK801. Male ICR mice, 8 weeks old, were randomly divided into groups, 10 mice in each group. Experimental design: control group, model group, low-dose guanosine group (0.5mg/kg), high-dose guanosine group (8mg/kg), short-term positive drug group (clozapine 2mg/kg), long-term positive drug Group (clozapine 2mg/kg). Among them, the low-dose guanosine group, the high-dose guanosine group, and the long-term positive drug group were given the corresponding drugs by gavage. The control group, the model group and the short-term positive drug group were given the same volume of normal saline once a day for 15 consecutive days. Gavage was administered on the last day. Among them, the short-term positive drug group was given clozapine 2 mg/kg, and the administration of other groups remained unchanged. One hour later, the control group was intraperitoneally injected with normal saline, and the other groups were intraperitoneally injected with the same volume of MK-801 (0.5 mg/kg). The computer records for 20 minutes immediately. During the experiment, the computer automatically recorded the total distance, average speed, total exercise time, resting time, central area time, central area movement distance, central area movement speed, central area resting time, peripheral area time, peripheral area movement distance, Multiple indicators such as the movement speed of the surrounding area and the resting time of the surrounding area. In addition, you can also record the animal's movement examples and time in the central area, inner area, and peripheral area, and calculate their percentage of the total movement distance and time. The total distance and average speed of exercise are used as the main indicators to evaluate autonomous activities.

The structure of clozapine is as follows:

The experimental results are shown in Figures 1.1 and 1.2, which show the effect of the compound of the present invention on the MK-801-induced mouse schizophrenia model.

The experimental results show that the compound of the present invention has a significant inhibitory effect on the spontaneous activities (Figure 1.1) and stereotyped behavior (Figure 1.2) induced by MK-801 in mice, and can be used as NMDA (N-methyl-D-aspartic acid) receptor More in-depth research on body inhibitors.

Test Example 2: The effect of the compound on 5-HTP-induced 5-HT syndrome and Serotonin syndrome (Serotonin syndrome) in rats

Dysfunction of the 5-HT system is related to a variety of neuropsychiatric diseases, including schizophrenia. 5-HT _2A receptor antagonists can increase dopaminergic transmission in the substantia nigra striatum and prefrontal cortex, thereby reducing the risk of EPS, and improve negative symptoms and cognitive impairment by increasing the release of DA and ACh in the prefrontal cortex. Most of the SS behavior of serotonin syndrome induced by drugs such as DOI and 5-HT releasing agents (such as 5-HT precursor 5-hydroxytryptophan, 5-HTP) is mediated by 5-HT _1A receptors. Head twitches and wet dog-like shaking are thought to be mediated through 5-HT ₂ receptors.

In this experiment, SD rats were selected to establish a 5-HTP-induced 5-HT syndrome model. Male SD rats, 8 weeks old, were randomly divided into groups, 10 rats in each group. Experimental design: control group, model group, low-dose guanosine group (0.75mg/kg), middle-dose guanosine group (2.5mg/kg), high-dose guanosine group (7.5mg/kg), positive drug group (hydrochloride hydrochloride) Heptidine (Cyp) 4.8mg/kg). Each dose of C2 and the positive drug was dissolved in 0.5% CMC, and the animals were given intragastrically 1 hour before the intraperitoneal injection of serotonin. Recorded for 1 hour immediately after intraperitoneal injection of serotonin. Statistics of shaking head behavior and wet dog-like shaking behavior. Record for 60 minutes immediately. During the experiment, the behaviors such as head shaking, body stretching, forefoot stepping, hind limb abduction, wet dog shaking, head twitching, etc. were recorded in the form of scores. Wet dog-like tremor was used as the main indicator to evaluate autonomous activities.

Cyproheptadine hydrochloride is represented by the following formula:

Score 60min continuously at 5min intervals

0=No such behavior

1 = Not obvious behavior

2 = Obvious behavior

3=Persistent and strong behavior

The number of wet dog shaking was recorded at 5 min intervals.

3.1. Specific experimental steps

1. Prepare compounds to be used freshly every day, cyproheptadine hydrochloride (4.8mg/kg), guanosine (0.75mg/kg, 2.5mg/kg, 7.5mg/kg) and 5-HTP (320mg/kg) are all dissolved in 0.9% saline.

2. On the day of the experiment, rats in the cyproheptadine group and guanosine group were orally administered cyproheptadine hydrochloride and guanosine respectively, and the model group was given a similar volume of NS. One hour later, 320 mg/kg 5-HTP was injected intraperitoneally to make the model.

3. After injection and modeling, immediately transfer the rat to an independent cage, and record the behavior of the rat by video recording directly above. The shooting time is 60 minutes.

4. Blind assessment of the rat's behavior by watching the filmed video by an unknowing observer: scoring head shaking, front paw stepping, hind limb abduction, tremor, hyperresponsiveness, etc., and wet dog-like shaking Behaviors are counted.

3.2 The experimental results are as follows

The experimental results are shown in Figure 2A-C. It can be seen that guanosine inhibits the wet dog-like shaking behavior induced by 5-HTP.

In this experiment, male SD rats were used to test the effects of different doses of guanosine on 5-HTP-induced serotonin syndrome. This experiment uses a single (320mg/kg) injection molding method.

In the form of a line graph, the number of wet dog tremors every 5 minutes from 0 minutes to 60 minutes of the experiment is depicted. At the 0th minute, 5-HTP was injected to create a model (see Figure 3A). During the experiment, it can be observed that 5-HTP (320mg/kg) induces strong serotonin syndrome behavior in rats. Wet dog-like tremors appeared about 2 minutes after injection, and the phenomenon gradually became severe, about 40 to The most severe is at 45 minutes. The bar graph in Figure 3B shows the total number of wet dog shakes (WDS) in rats. Statistics show that compared with the model group, guanosine (0.75mg/kg, 2.5mg/kg, 7.5mg/ kg) dose-dependently reduced the number of wet dog-like tremors induced by 5-HTP (mediated by 5-HT ₂ receptor). As a positive control, cyproheptadine (4.8 mg/kg) also significantly inhibited WDS induced by 5-HTP. Head shaking, body stretching, forefoot stepping, hind limb abduction and other behaviors are caused by the excitement of 5-HT _1A receptors. Figure 3C shows the scores of other SS behaviors (mediated by the 5-HT _1A receptor). It can be seen that guanosine inhibits other SS behaviors caused by the excitation of the 5-HT _1A receptor.

The experimental results are shown in Figure 2 (AC), which shows the effects of the compounds of the present invention such as guanosine on 5-HTP-induced behaviors of rats with 5-HT syndrome. The experimental results show that the compound of the present invention has inhibitory effects on 5-HTP-induced head shaking, body flattening, forefoot stepping, hindlimb abduction, wet dog-like shaking, head twitching and other behaviors in rats. Specifically, the compound of the present invention is a bird Glycosides can significantly inhibit 5-HTP (320mg/kg)-induced strong serotonin (5-HT) syndrome behaviors in rats (including most SS behaviors mediated by 5-HT _1A receptors, and through 5-HT _1A receptors) HT ₂ receptor-mediated head twitching and wet dog-like shaking), it can be seen that the compounds of the present invention can be used as 5-HT receptor inhibitors.

Test Example 3. Activity test of the compound of the present invention on 5-HT _1A receptor

5-HT _1A receptor is a G protein-coupled receptor, which can be coupled to Gi/o/protein after activation, thereby inhibiting the activity of adenylate cyclase.

3.1.5-HT _1A receptor experimental procedure

1. Detect the effect of 5-HT on SH-SY5Y cAMP; add different concentrations of 5-HT (10 ^-14 , 10 ^-12 , 10 ^-10 , 10 ^-8 , 10 ^-6 , 10 ^-5 ) to SH-SY5Y The change of cAMP in SH-SY5Y with the change of 5-HT concentration.

2. The detection compound guanosine stimulates or inhibits cAMP at the selected 5-HT concentration. Guanosine was incubated at room temperature for 30 minutes, and 5-HT was added to test the same change of cAMP at 10 ^-8 M.

3.2. Experimental results

The results are shown in Figure 3E-F. As shown in Figure 3E, it can be seen that 5-HT did not cause changes in cAMP in SH-SY5Y cells, possibly because the cells are in a dynamic change of self-regulation. As shown in Figure 3F, guanosine increased cAMP, and this result indicates that guanosine exhibits an antagonistic effect on 5-HT _1A receptors.

3.3. Experimental conclusion

The experimental results show that the compound of the present invention such as guanosine may have an antagonistic effect on 5-HT _1A , which is consistent with the result of 5-HTP-induced serotonin syndrome in Test Example 2.

Test Example 4. The effect of the compound of the present invention on PI3K/Akt signaling pathway

Guanosine has a regulatory effect on the serotonin system. 5-HT receptors mediate various behavioral responses of SS and most 5-HT receptors are coupled to G protein. Therefore, this experimental example further tested the effect of guanosine on the downstream signaling pathway of G protein. In this test example, WB (Western Blot) was used to study the PI3K/Akt signaling pathway of cells and tissues.

4.1 Experimental procedure

1. Cell sample preparation steps

SH-SY5Y cells were seeded in a 6-well plate at a density of 3×10 ⁵ cells/well, and cultured in DMEM/F12 (1:1) containing 10% FBS for 24 hours. In order to evaluate the effect of guanosine on the PI3K/Akt signaling pathway, cells were pretreated with PI3K inhibitor LY294002 (10 μM) for 30 minutes, and then guanosine (0, 5, 50 μM) was added and incubated for 60 minutes, respectively. To study the effect of guanosine on G _i/o protein-coupled receptors, 100ng/mL of G _i/o receptor inhibitor Pertussis toxin (PTX, CAS No.: 70323-44-) was added to the cell culture medium. ) Pre-treatment for 12 hours, then add guanosine (0, 5, 50 μM) and incubate for 60 minutes. Aspirate the culture medium, wash the cells gently with D-Hanks (buffer) pre-cooled at 4°C, and discard D-Hanks. Add 100μL/well of protein lysis buffer, lyse on ice for 30 minutes, while continuously pipetting the cells with a pipette, taking care to avoid bubbles as much as possible. After lysis, transfer the suspension to a 1.5mL centrifuge tube. Centrifuge for 10 minutes at 8000g at 4°C. Discard the supernatant and leave 5 μL for protein quantification. Add 4× loading buffer to the remaining part in proportion to adjust the concentration to 1×, and mix by pipetting. Boil for 7 minutes in a metal bath at 100°C. After cooling, divide and store in -80℃ refrigerator.

The structure of LY294002 is as follows

2. Brain tissue sample preparation steps

SD rats were given guanosine (5 mg/kg) once a day for 7 consecutive days, and were sacrificed by decapitation on the 7th day. Quickly remove the brain tissue and separate the cortex on ice. Transfer the cortex to the tissue lysate containing phosphatase inhibitors and protease inhibitors, and grind them appropriately with a Dunes homogenizer on ice to homogenize them, paying attention to minimize friction and heat during the process. After lysis, as with cell samples, save 5μL for protein quantification, and dilute the rest with 4× loading buffer, boil and denature at 100°C, and store in aliquots.

3.WB

WB follows the steps of electrophoresis-transfer-blocking and hybridization-luminescence development.

4.2 Experimental results

The experimental results are shown in Figure 4A-C.

Figure 4A shows that after 7 consecutive days of oral administration of guanosine, the Akt phosphorylation level in rat cortex was significantly increased compared with the control group.

In order to further explore the changes of PI3K/Akt pathway, SH-SY5Y cells were pretreated with PI3K inhibitor LY294002 (20μM) for 30 minutes, and then guanosine (0 means control group, 5, 50μM) was added and incubated for 60 minutes. The results are shown in Figure 4B. It can be seen from Figure 4B that compared with the control, guanosine (50μM) significantly increased the phosphorylation of Akt in the cells; the LY294002 treatment group (ie, the LY+guanosine (5 or 50μM) group) was compared Compared with the untreated control group (ie, the guanosine (5 or 50μM) group), the phosphorylation of Akt was significantly reduced, indicating that LY294002 inhibited the activation of Akt caused by guanosine.

In order to study whether guanosine acts on Gi/o protein-coupled receptors, the cells were pretreated with PTX (Gi/o inhibitor), and then guanosine (0, control group, 5, 50 μM) was added and incubated for 60 minutes. The results are shown in Figure 4C, and it can be seen from Figure 4C that guanosine (50 μM) significantly increased the phosphorylation of Akt in the cells compared with the control. Compared with the corresponding untreated group, the phosphorylation of Akt in the PTX treatment group was significantly reduced.

4.3 Experimental conclusion

Experimental results showed that guanosine treatment caused Akt activation and phosphorylation in rat cortex. In addition, PI3K inhibitor LY294002 and G _i/o receptor inhibitor PTX reduced the increase in Akt phosphorylation in SH-SY5Y cells. These results indicate that guanosine may activate the PTX-sensitive G _i/o coupled PI3K/Akt signal.

All documents mentioned in the present invention are cited as references in this application, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

A use of guanosine and its derivatives, or pharmaceutically acceptable salts, or enantiomers, diastereomers or racemates thereof, or prodrugs thereof, characterized in that , The use is one or more uses selected from the following group:

(a) Used to prepare a composition or preparation for the treatment and/or prevention of mental illness, and/or for alleviating the symptoms and/or physiological characteristics of mental illness;

(b) Used as NMDA (N-methyl-D-aspartic acid) inhibitor;

(c) Used as a 5-HT inhibitor;

(d) Preparation for the treatment and/or prevention of diseases induced by 5-HT and/or its precursors and/or for alleviation and/or alleviation of diseases induced by 5-HT and/or its precursors drug;

(e) For the preparation of drugs for the treatment and/or prevention of diseases mediated by PI3K/Akt signaling pathway and/or for alleviating and/or alleviating diseases and diseases mediated by PI3K/Akt signaling pathway;

(f) Used to activate PI3K/Akt signal pathway;

(g) For the preparation of drugs for treating and/or preventing diseases mediated by 5-HT receptors and diseases mediated by 5-HT receptors; and/or

(h) As a 5-HT receptor antagonist;

And the guanosine and its derivatives are shown in formula I,

among them,

R 1 and R 2 are each independently selected from: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl-C1-C3 alkyl, substituted or unsubstituted C1-C6 alkane Ylformyl, substituted or unsubstituted C6-C10 aryl-formyl;

Q is unsubstituted or substituted by one or more R groups, monosaccharides, disaccharides or trisaccharides; wherein each of R is independently selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or Unsubstituted C6-C10 aryl-C1-C3 alkyl, substituted or unsubstituted C1-C3 alkylformyl, substituted or unsubstituted C6-C10 aryl-formyl;

Unless otherwise specified, the said substitution means that one or more hydrogens in the group are replaced by a substituent selected from the group consisting of halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 Aryl-C1-C3 alkyl, C1-C3 alkylformyl, C6-C10 aryl-formyl.
The use according to claim 1, wherein the mental illness includes: mania, and/or schizophrenia.
The use according to claim 2, characterized in that:

The mania includes: hypomania and/or recurrent mania; and/or

The schizophrenia includes: paranoid schizophrenia, adolescent schizophrenia, catatonic schizophrenia, simple schizophrenia, undifferentiated schizophrenia, and residual schizophrenia.
The use according to claim 1, wherein the guanosine and its derivatives are represented by formula II,

among them,

The definitions of R 1 and R 2 are the same as in claim 1;

R 3 , R 4 and R 5 are each independently selected from: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl-C1-C3 alkyl, substituted or unsubstituted C1 -C3 alkyl formyl, substituted or unsubstituted C6-C10 aryl-formyl.
The use according to claim 1, wherein the guanosine and its derivatives are guanosine of formula III
A guanosine derivative, characterized in that the guanosine derivative is as shown in formula IV,

among them,

R a and R b are independently selected from: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl-C1-3 alkyl, substituted or unsubstituted C1-C3 alkyl Acyl, substituted or unsubstituted C6-C10 aryl-formyl;

Z is unsubstituted or substituted by one or more R groups, monosaccharides, disaccharides or trisaccharides; wherein each R is independently selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or Unsubstituted C6-C10 aryl-C1-3 alkyl, substituted or unsubstituted C1-C3 alkylformyl, substituted or unsubstituted C6-C10 aryl-formyl;

Unless otherwise specified, the said substitution means that one or more hydrogens in the group are replaced by a substituent selected from the group consisting of halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 Aryl-C1-3 alkyl, C1-C3 alkylformyl, C6-C10 aryl-formyl;

And, the guanosine derivative does not include a compound selected from the following group:
The guanosine derivative of claim 6, wherein the guanosine derivative is represented by formula V,

among them,

The definitions of R a and R b are the same as in claim 6;

R c , R d and R e are each independently selected from: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl-C1-3 alkyl, substituted or unsubstituted C1 -C3 alkylformyl, substituted or unsubstituted C6-C10 aryl-formyl; and R c , Rd and R e are not H at the same time.
A pharmaceutical composition, characterized in that:

The composition comprises (i) a first active ingredient, which is the guanosine derivative according to claim 6, and (ii) a pharmaceutically acceptable carrier; or

The composition includes (i1) a first active ingredient, the first active ingredient being the guanosine and its derivatives described in claim 1, (i2) a second active ingredient, and the second active ingredient The ingredients include: other drugs for treating and/or preventing mental illness, drugs for preventing and/or relieving symptoms of mental illness, NMDA inhibitors, 5-HT inhibitors, or combinations thereof, and (ii) pharmaceutically acceptable Accepted carrier.
A method for inhibiting NMDA receptors, which is characterized in that it comprises the steps of making the target and the guanosine and its derivatives described in claim 1, the guanosine derivatives according to claim 6, and/ Or contact with the pharmaceutical composition of claim 8 to inhibit the NMDA receptor.
A method for inhibiting 5-HT receptors, which is characterized in that it comprises the steps of: making the target and the guanosine and its derivatives described in claim 1 and the guanosine derivatives according to claim 6 And/or contact with the pharmaceutical composition of claim 8 to inhibit 5-HT receptors.
A method for activating the PI3K/Akt signaling pathway, which is characterized in that it comprises the steps of: making the target match the guanosine and its derivatives according to claim 1, and the guanosine derivative according to claim 6. And/or contact with the pharmaceutical composition of claim 8 to inhibit 5-HT receptors.
A method for treating and/or preventing and alleviating mental illness and/or alleviating symptoms of mental illness, which is characterized by comprising the step of: administering a therapeutically effective amount of the guanine nucleus as claimed in claim 1 to a subject in need Glycosides and derivatives thereof, guanosine derivatives as claimed in claim 6, and/or pharmaceutical compositions as claimed in claim 8.
A method for treating and/or preventing diseases mediated by 5-HT receptors, and/or alleviating and/or alleviating diseases mediated by 5-HT receptors, characterized in that it comprises the steps: The subject is administered a therapeutically effective amount of the guanosine and its derivatives as described in claim 1, the guanosine derivatives as described in claim 6, and/or the drug as claimed in claim 8. combination.
The method of claim 13, wherein the diseases mediated by 5-HT receptors include: serotonin syndrome, 5-HT syndrome, or a combination thereof; and/or the 5-HT Receptor-mediated conditions include: serotonin syndrome behavior (SS behavior), head twitching, and/or wet dog shaking.