Compositions and methods for sedation

Abstract

Methods of sedation using active peptides are provided, as are compositions comprising the peptides and uses of the peptides.

Description

Compositions and methods for sedation

[0001] This disclosure claims priority to Chinese patent application CN202410051028.1 filed on January 15, 2024, and the entire contents of the aforementioned patent application are incorporated into this disclosure by reference. Technical Field

[0002] The present disclosure belongs to the technical field of pharmaceutical compounds, and particularly relates to the sedative use of active peptides. Background Art

[0003] Sedatives are drugs that have an inhibitory effect on brain nerve activity. They are needed in many cases. For example, they suppress the normal activity level of the central nervous system to achieve surgical sedation; they inhibit excessive excitement of the central nervous system, help relieve people's anxiety, treat mental tension, and calm agitation symptoms caused by mental illness, neurological diseases or other diseases.

[0004] Currently, commonly used sedatives include benzodiazepines Non-benzodiazepines These sedatives, such as midazolam, etomidate, propofol, and dexmedetomidine, all have their own drawbacks. For example, long-term use of midazolam can lead to cumulative effects, resulting in respiratory depression and delayed awakening; etomidate can easily cause muscle tremors and injection pain, and long-term use can inhibit cortisol secretion; propofol can significantly suppress the heart and lungs; and dexmedetomidine can have adverse reactions such as hypotension and bradycardia. Therefore, new sedatives are needed to provide patients with more medication options.

[0005] Ideal sedatives should have rapid onset of action, rapid recovery after discontinuation, anterograde amnesia, low incidence of adverse reactions, predictable dose-response, no accumulation, no toxicity, minimal respiratory and circulatory suppression, and metabolism independent of liver and kidney function. There is a strong demand for new sedatives in clinical practice.

[0006] Brief Description

[0007] The present disclosure aims to solve, at least to some extent, one of the technical problems in the related art. In a first aspect, the present disclosure provides an active peptide comprising the amino acid sequence KKNRNKLRRQHSY (SEQ ID NO: 1) or consisting of the amino acid sequence shown in SEQ ID NO: 1, or a functionally equivalent variant thereof, for use in the preparation of a medicament for sedation or prevention and / or treatment of diseases or conditions associated with a non-sedated state.

[0008] In a second aspect, the present disclosure provides an active peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 1, or a functionally equivalent variant thereof, for use in sedation or prevention and / or treatment of diseases or conditions associated with a non-sedated state.

[0009] In some specific embodiments, the functionally equivalent variant of the active peptide has 1, 2 or 3 conservative amino acid substitutions, additions or deletions relative to the active peptide, such as hydrophobic amino acid substitutions or additions.

[0010] The hydrophobic amino acids that can be selected include tryptophan, phenylalanine, valine, leucine, isoleucine, alanine, proline and methionine (methionine) and the like.

[0011] In some specific embodiments, the active peptide or its functionally equivalent variant has a cell-penetrating peptide sequence added to its C-terminus or N-terminus.

[0012] In some specific embodiments, the cell-penetrating peptide sequence is selected from: a TAT sequence, a MAP sequence, an MTS sequence, or an R9 sequence.

[0013] In some specific embodiments, the cell-penetrating peptide sequence is a TAT sequence added to the N-terminus.

[0014] In some specific embodiments, the active peptide is an active peptide comprising the amino acid sequence YGRKKRRQRRRKKNRNKLRRQHSY (SEQ ID NO: 2).

[0015] In some specific embodiments, the amino acid sequence of the active peptide is the active peptide (S1) of YGRKKRRQRRRKKNRNKLRRQHSY (SEQ ID NO: 2).

[0016] In some specific embodiments, the active peptide is a functionally equivalent variant of S1 with an amino acid sequence of SEQ ID NO: 2, and the functionally equivalent variant has 1, 2 or 3 conservative amino acid substitutions, additions or deletions relative to S1 with an amino acid sequence of SEQ ID NO: 2.

[0017] In some embodiments, the functionally equivalent variant has at least about 70%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or more sequence identity with the active peptide.

[0018] In some embodiments, the sedation is sedation during intensive care.

[0019] In some embodiments, the sedation is non-intubation intraoperative or preoperative sedation.

[0020] In some embodiments, the sedation is sedation during or prior to a non-intubation physical examination / procedure for diagnosis or treatment of a disease or condition.

[0021] In some embodiments, the sedation is anesthesia induction.

[0022] In some embodiments, the sedation is sedation to treat agitation symptoms resulting from a psychiatric, neurological, or other disorder.

[0023] In some embodiments, the sedation comprises anxiolysis, and / or anticonvulsant.

[0024] In some embodiments, the psychiatric or neurological disease or other disease is selected from Alzheimer's disease, schizophrenia, bipolar disorder, schizoaffective disorder, dementia, personality disorder, anxiety disorder, panic disorder, post-traumatic stress disorder, autism spectrum disorder, psychoactive substance dependence or intoxication, alcohol or drug withdrawal, brain trauma, hyperthyroidism, severe pain, metabolic disorder, hypoxia, drug intoxication or electrolyte imbalance.

[0025] In some embodiments, the sedation is sedation and tranquilization, promotion of relaxation, induction of sleep, extension of sleep time, and / or shortening of time to fall asleep in patients with sleep disorders.

[0026] In some specific embodiments, the non-sedation-related disease or condition is selected from the group consisting of anxiety, nervousness, convulsions, and insomnia. In some further embodiments, the non-sedation-related disease or condition does not include depression.

[0027] In a third aspect, the present disclosure provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the active peptide as described above and / or its functionally equivalent variant and a pharmaceutically acceptable excipient.

[0028] In some embodiments, the pharmaceutical composition comprises one, two, or more additional compounds for sedation.

[0029] In a fourth aspect, the present disclosure provides a method for sedation or for preventing and / or treating a disease or condition associated with a non-sedated state, comprising administering to a subject the active peptide and / or its functionally equivalent variant as described above, or administering the pharmaceutical composition as described above.

[0030] In some embodiments, the subject to which the active peptides of the present disclosure are administered is a mammal, preferably a human.

[0031] In some embodiments, the present disclosure provides a method for sedation or prevention and / or treatment of diseases or symptoms associated with a non-sedated state, comprising administering an effective amount of S1 (designated S1) having an amino acid sequence of SEQ ID NO: 2 to a subject in need thereof, so that the subject reaches at least a mildly hypoactive sedated state.

[0032] Without being bound by theory, the inventors of the present disclosure surprisingly found that the active peptides of the present disclosure can induce sedation, including by suppressing the normal activity level of the central nervous system and / or suppressing the overexcitation of the central nervous system to achieve sedation. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1. Statistical results of sedation levels in rats of each group after receiving S1 via tail vein infusion with normal saline, low-dose S1, medium-dose S1, and high-dose S1, respectively.

[0034] Figure 2. Statistical results of sedation onset time after rats in each group received normal saline, low-dose S1, medium-dose S1, and high-dose S1 via tail vein infusion.

[0035] Figure 3. Statistical results of sedation duration after rats in each group received normal saline, low-dose S1, medium-dose S1, and high-dose S1 via tail vein infusion.

[0036] Figure 4. Statistical results of sedation scores of rats in each group after receiving normal saline and different doses of S1 by tail vein injection.

[0037] Detailed description

[0038] The disclosure of this application provides various compositions, methods, and uses for sedation.

[0039] As used herein, the term "mammal" refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, cats, cows, horses, sheep, pigs, goats, rabbits, and the like.

[0040] As used herein, the term "effective amount" refers to a dose that can achieve a sedative effect on a subject, more specifically, at least a mildly hypoactive sedative state. In one embodiment, a therapeutically effective amount includes, but is not limited to, about 0.1-1000 mg / kg body weight, preferably 1-100 mg / kg body weight, and more preferably 10-50 mg / kg body weight.

[0041] Peptides of the present disclosure:

[0042] In an exemplary embodiment, peptides suitable for the present disclosure include the active peptide KKNRNKLRRQHSY (SEQ ID NO: 1) or a sequence (or variant) thereof having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99% or 100% identity. Also included are sequences (or variants) having YGRKKRRQRRRKKNRNKLRRQHSY (SEQ ID NO: 2) or a sequence (or variant) thereof having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99% or 100% identity. Preferably, the variants have 1, 2 or 3 conservative amino acid substitutions, additions or deletions and exhibit substantially similar in vivo or in vitro activity to the peptide examples of the present disclosure.

[0043] The active peptide KKNRNKLRRQHSY (SEQ ID NO: 1) in the present disclosure is named S3.

[0044] Variants of the peptides disclosed herein are also within the scope of the present disclosure. A peptide variant refers to an amino acid sequence in which one or more amino acids are altered. A variant can have "conservative" changes, wherein the substituted amino acids have similar structural or chemical properties, such as replacing leucine with isoleucine. Alternatively, a variant can have "non-conservative" changes, such as replacing glycine with tryptophan. Similar minor changes can also include amino acid deletions or insertions, or both. A specific form of a "variant" peptide is a "functionally equivalent" peptide, i.e., a peptide that exhibits substantially similar in vivo or in vitro activity to the peptide examples disclosed herein. Guidance for determining which amino acid residues can be substituted, inserted, or deleted without losing biological or immunological activity can be found using computer programs well known in the art, such as DNASTAR software (DNASTAR, Inc., Madison, WI). In addition, specific guidance is provided below, including those provided within the cited references, which are incorporated herein by reference.

[0045] In other embodiments, the specific position of the named residue can be varied slightly while still existing at a structurally and functionally analogous position in the peptide (see Chang, Y., et al., Biochemistry 37:3258-3271 (1998)).

[0046] In addition, the peptides of the present disclosure may further comprise a membrane-penetrating peptide at its N-terminus or C-terminus that can guide the peptides of the present disclosure to cross the blood-brain barrier and the nerve cell membrane. Suitable membrane-penetrating peptides known in the art can be used in the present disclosure as long as they can guide the peptides of the present disclosure to cross the blood-brain barrier and the nerve cell membrane.

[0047] Without being bound by theory, surprisingly, the inventors of the present disclosure have found that membrane-penetrating peptides can significantly enhance the inhibitory effect of S3 on brain neural activity. Exemplary membrane-penetrating peptides can be selected from human HIV-1 Tat protein fragment (TAT) sequence ("GRKKRRQRRR (SEQ ID NO: 3)", "YGRKKRRQRRR (SEQ ID NO: 4)", "YGRKKRRQRRRPPQ (SEQ ID NO: 5)" or "GRKKRRQRRRQ (SEQ ID NO: 6)"), model amphipathic peptide (MAP) sequence ("KLALKLALKALKAALKLA (SEQ ID NO: 7)"), membrane translocating peptide (MTS) sequence ("AAVALLPAVLLALLAP (SEQ ID NO: 8)") or R9 ("RRRRRRRRR (SEQ ID NO: 9)") sequence. In a particularly preferred embodiment, the membrane-penetrating peptide of the present disclosure is a TAT sequence. In one exemplary embodiment, the peptide of the present disclosure comprises or consists of the sequence YGRKKRRQRRRKKNRNKLRRQHSY (SEQ ID NO: 2) (designated as S1). In some specific embodiments, the cell-penetrating peptide is "YGRKKRRQRRR (SEQ ID NO: 4)".

[0048] In an exemplary embodiment, the peptide of the present disclosure is a short-chain peptide with strong hydrophobicity, which enables it to easily cross the blood-brain barrier and nerve cell membrane with the help of a membrane-penetrating peptide.

[0049] The peptides disclosed herein have a sedative effect. In some exemplary embodiments, the peptides disclosed herein can be used to suppress the normal activity level of the central nervous system, and thus can be applied to sedation during intensive care, sedation during or before non-intubated surgery, sedation during or before the diagnosis or treatment of non-intubated physical examinations / operations, anesthesia induction, etc. In other exemplary embodiments, the peptides disclosed herein can be used to suppress excessive excitability of the central nervous system, and thus can be used for non-sedated states such as anxiety, mental tension, convulsions, or insomnia, as well as for sedation of agitation symptoms caused by mental illness, neurological diseases, or other diseases, and for sedation, relaxation promotion, sleep induction, prolonged sleep time, shortened sleep onset time, etc., in patients with sleep disorders. Among them, the mental illness, neurological disease or other disease can be Alzheimer's disease, schizophrenia, bipolar disorder, schizoaffective disorder, dementia, personality disorder, anxiety disorder, panic disorder, post-traumatic stress disorder, autism spectrum disorder, psychoactive substance dependence or poisoning, alcohol or drug withdrawal, brain trauma, hyperthyroidism, severe pain, metabolic disorder, hypoxia, drug poisoning or electrolyte disorder.

[0050] For the purpose of promoting the understanding of the principle of the present disclosure, reference will now be made to the embodiments illustrated in the accompanying drawings and the embodiments will be described in detail. However, these descriptions are not intended to limit the scope of the present disclosure in any way.

[0051] Example 1:

[0052] The effects of different doses of S1S1 on inducing sedation in rats were evaluated.

[0053] Materials and Methods

[0054] A. 120 SD rats were randomly divided into saline control, S1 low-dose (10 mg / kg) treatment, S1 medium-dose (20 mg / kg) treatment, and S1 high-dose (30 mg / kg) treatment groups, with half males and half females.

[0055] B. Rats in each group received normal saline, low-dose S1, medium-dose S1, and high-dose S1 intravenous infusion of 4 mL / kg.

[0056] C. After the intravenous infusion, each rat was observed for 4 hours for behavioral activity.

[0057] D. When calculating the degree of induced sedation, if the rat did not show sedation, it was recorded as 0; when calculating the onset time of induced sedation, if the rat did not show sedation, it was deleted; when calculating the duration of induced sedation, if the rat did not show sedation, it was recorded as 0.

[0058] S1S1 evaluated the sedative effect of S1 by reducing activity in Sprague-Dawley rats. The intensity, onset, and duration of sedation induced by S1 at different doses were evaluated. One hundred and twenty SPF Sprague-Dawley rats, half male and half female, were randomly assigned to a saline group, a low-dose S1 group, a medium-dose S1 group, and a high-dose S1 group, with 30 animals per group (half male and half female). After each group received a tail vein injection of the corresponding drug, the rats' general activity was observed for four hours. The statistical results of the sedation success rate are shown in Table 1.

[0059] Table 1 Statistical results of sedation induction success rate

[0060] The statistical results in Table 1 show that animals in the saline group showed normal activity, with a sedation-induction success rate of 0 / 30. All animals in the low-dose S1 group showed normal activity, with a sedation-induction success rate of 0 / 30. Animals in the medium-dose S1 group generally showed mildly decreased activity, with a sedation-induction success rate of 20 / 30. All animals in the high-dose S1 group showed mildly decreased activity, with a sedation-induction success rate of 30 / 30. S1 treatment significantly induced sedation in SD rats at both medium and high doses, with the sedation success rate increasing with increasing dose.

[0061] The statistical results of sedation levels are shown in Figure 1. The results in Figure 1 show that rats in the saline group had normal activity and a sedation level of 0 ± 0; rats in the low-dose S1 group had normal activity and a sedation level of 0 ± 0; rats in the medium-dose S1 group generally had slightly reduced activity, with an average sedation level of 0.7 ± 0.1; and rats in the high-dose S1 group had a mildly reduced activity, with an average sedation level of 1 ± 0. The medium and high doses of S1 induced significant sedation, and the sedation level increased significantly with increasing dose.

[0062] The statistical results of the sedation onset time are shown in Figure 2. The statistical results in Figure 2 show that the rats in the saline group had normal activity and no sedation; the rats in the low-dose S1 group had normal activity and no sedation; the rats in the medium-dose S1 group generally had slightly reduced activity, with an average sedation onset time of 4.95±0.4 minutes; and the rats in the high-dose S1 group had slightly reduced activity, with an average sedation onset time of 3.97±0.34 minutes. The medium and high doses of S1 had a significant sedative effect, and the onset time of sedation was significantly shortened with increasing doses.

[0063] Figure 3 shows the statistical results of the duration of induced sedation. The results in Figure 3 indicate that rats in the saline group showed normal activity and no sedation; rats in the low-dose S1 group showed normal activity and no sedation; rats in the medium-dose S1 group generally showed mild decrease in activity, with an average duration of induced sedation of 12.15 ± 0.88 minutes; and rats in the high-dose S1 group showed mild decrease in activity, with an average duration of induced sedation of 21.73 ± 3.15 minutes. The medium and high doses of S1 induced significant sedation, and the duration of induced sedation was significantly prolonged with increasing doses.

[0064] Therefore, in SD rats, S1 can induce a sedative effect manifested by decreased activity, and this sedative effect increases with increasing S1 doses. Specifically, increasing S1 doses significantly enhance the degree of sedation, shorten the onset of sedation, prolong the duration of sedation, and significantly improve the success rate of sedation. In summary, S1 can be used for sedation or to prevent and / or treat diseases or symptoms associated with non-sedated states.

[0065] Example 2:

[0066] The sedation depth scores of SD rats were evaluated after taking different doses of S1.

[0067] Normal SD rats were injected via tail vein with physiological saline and various doses of S1 (10 mg / kg, 15 mg / kg, 30 mg / kg, 40 mg / kg, and 60 mg / kg). The depth of sedation was scored based on six criteria: spontaneous activity level, antidromic reflex, palpebral reflex, noise reflex, mouth-opening resistance, and overall performance. The scoring table is shown in Table 2.

[0068] Table 2 Symptoms and sedation scores

[0069] The results are shown in Figure 4. S1, at a dose of 15 mg / kg, began to produce a sedative effect in rats, with a score of approximately 2.5 points, primarily manifested by spontaneous activity / abnormal posture (prone position) and abnormal overall appearance (wakefulness with decreased activity). Sedation scores increased with increasing drug doses. At doses of 40 mg / kg and 60 mg / kg, S1 further resulted in a sluggish eyelid reflex, weakened counteraction, and diminished startle response. In summary, the depth of S1-induced sedation in rats increased with increasing dose.

[0070] Example 3:

[0071] The success rates of sedation induction were compared after the SD rats in the normal experiment received the same amount of S1 (9 μmol / kg) of S1, S2 and S3 injected into the tail vein.

[0072] The sedative effects of S1, S2, and S3, which induce hypoactivity in SD rats, were evaluated by observing their general activity. Twenty-seven SPF male SD rats were randomly assigned to the S1, S2, and S3 groups. Each group received a tail vein injection of 4 mL / kg of the corresponding drug, and their general activity was observed for four hours. The success rate of sedation induction is shown in Table 3.

[0073] Table 3 Statistical results of sedation induction success rate

[0074] The statistical results in Table 3 show that the success rate of sedation induction in the S1 group was 12 / 12, the S2 group was 0 / 3, and the S3 group was 0 / 12. In other words, only S1 significantly induced sedation in rats via tail vein injection; neither S2 nor S3 was able to induce sedation in SD rats.

[0075] Example 4:

[0076] The inhibitory effects of different doses of S1 on hNMDA receptor ion channel activity were evaluated.

[0077] HEK-293 cells stably expressing hNMDAR were cultured in DMEM supplemented with 10% fetal bovine serum, 100 μg / mL Zeocin, and 10 μg / mL Blastincidin at 37°C and 5% CO2. To maintain electrophysiological activity, the cell density must not exceed 80%.

[0078] Before the patch clamp test, cells were separated with 0.25%-Trypsin-EDTA and 1.5×10 4 Cells were plated on coverslips and cultured in 24-well plates (final volume: 500 μL). Tetracycline was added for induction and 1 mM DAP-5 was added. After 18 hours, the assay was performed.

[0079] After whole-cell seal was formed, the cell membrane voltage was clamped at -70 mV, and continuous drug administration was used for recording in the gap-free mode. 10 μM Glycine + 10 μM L-Glutamate, 10 μM Glycine + 10 μM L-Glutamate, and mixtures of test substances at different concentrations were sequentially sprayed on the cell surface to observe the effects of drugs on the hNMDA inward current.

[0080] The results showed that S1 inhibition of the hNMDA receptor inward current exceeded 50% only when the concentration was >100 nM; and DAP-5 inhibition of the primary hNMDA receptor inward current exceeded 50% only when the positive control concentration was >20 μM. The inhibitory effect of S1 on the hNMDA receptor inward current was approximately 200 times greater than that of DAP-5, significantly higher than that of DAP-5. This further demonstrates that S1 can effectively suppress central nervous system activity, thereby inducing sedation.

[0081] Example 5

[0082] The effects of different doses of S1 and KKNRNKLRRQHSY (SEQ ID NO: 1) S3 functional peptides on inhibiting the activity of hNMDA receptor ion channels were evaluated.

[0083] The test method is the same as that of Example 4. The statistical results of the hNMDA receptor inhibition rates of S1 and S3 functional peptides at different doses are shown in Table 4.

[0084] Table 4 Inhibition rate of hNMDA receptors by different doses of S1 and S3 functional peptides

[0085] The results in Table 4 show that at the same drug concentration, both S1 and S3 functional peptides have inhibitory effects on hNMDA receptors, and the inhibition rate of S3 functional peptide on hNMDA receptors is significantly lower than that of S1. This further indicates that both S1 and S3 functional peptides can effectively inhibit central nervous system activity levels, thereby inducing sedation, and S1 is more effective in inducing sedation.

[0086] Although various embodiments of the compositions and methods for sedation have been described herein in considerable detail, such embodiments are provided merely as non-limiting examples of the disclosure described herein. Therefore, those skilled in the art will appreciate that various changes and modifications may be made to the present invention without departing from the scope of the invention. Indeed, this disclosure is not intended to be exhaustive or to limit the scope of the invention.

[0087] Furthermore, in the description of representative embodiments, the present disclosure has presented the methods and / or processes of the present invention in a specific order of steps. However, the methods or processes should not be limited to the specific order of steps described. Other order of steps are possible. Therefore, the specific order of steps disclosed herein should not be construed as limiting the present invention. Furthermore, the disclosure of the methods and / or processes should not be limited to performing their steps in the order described. Such an order can be varied and still be within the scope of the present invention.

Claims

1. Use of an active peptide comprising the amino acid sequence KKNRNKLRRQHSY (SEQ ID NO: 1) or consisting of the amino acid sequence shown in SEQ ID NO: 1, or a functionally equivalent variant thereof, in the preparation of a medicament for sedation or prevention and / or treatment of a disease or disorder associated with a non-sedated state.

2. Use of an active peptide comprising the amino acid sequence shown in SEQ ID NO: 1 or consisting of the amino acid sequence shown in SEQ ID NO: 1, or a functionally equivalent variant thereof, in sedation or prevention and / or treatment of a disease or disorder associated with a non-sedated state.

3. The use according to claim 1 or 2, wherein, The functionally equivalent variant of the active peptide has 1, 2 or 3 conservative amino acid substitutions, additions or deletions relative to the active peptide, such as hydrophobic amino acid substitutions or additions.

4. The use according to any one of claims 1 to 3, wherein, The active peptide or its functionally equivalent variant has a transmembrane peptide sequence added to its C-terminus or N-terminus.

5. The use according to claim 4, wherein, The transmembrane peptide sequence is selected from: TAT sequence, MAP sequence, MTS sequence or R9 sequence.

6. The use according to claim 5, wherein, The transmembrane peptide sequence is the TAT sequence added to the N-terminus.

7. For the use according to claim 6, wherein, The active peptide is an active peptide comprising the amino acid sequence YGRKKRRQRRRKKNRNKLRRQHSY (SEQ ID NO: 2).

8. The use according to claim 7, wherein, The active peptide has the amino acid sequence YGRKKRRQRRRKKNRNKLRRQHSY (SEQ ID NO: 2).

9. The use according to claim 8, wherein The active peptide is a functionally equivalent variant of the active peptide having the amino acid sequence SEQ ID NO: 2, and the functionally equivalent variant has 1, 2 or 3 conservative amino acid substitutions, additions or deletions relative to the active peptide having the amino acid sequence SEQ ID NO:

2.

10. The use according to any one of claims 1-9, wherein, The functionally equivalent variant has at least about 70%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or higher sequence identity with the active peptide.

11. The use according to any one of claims 1 to 10, wherein, The sedation is sedation during intensive care, and / or sedation during or before non-intubated surgery, and / or sedation during or before the diagnosis or treatment of non-intubated physical disease examinations / operations, and / or anesthesia induction.

12. The use according to any one of claims 1-10, wherein, The sedation is sedation of agitation symptoms caused by mental diseases, neurological diseases or other diseases, and / or sedation, promoting relaxation, inducing sleep, prolonging sleep time, and / or shortening sleep onset time for patients with sleep disorders; Optionally, the mental disease, neurological disease or other disease is selected from Alzheimer's disease, schizophrenia, bipolar disorder, schizoaffective disorder, dementia, personality disorder, anxiety disorder, panic disorder, post-traumatic stress disorder, autism spectrum disorder, psychoactive substance dependence or intoxication, alcohol or drug withdrawal, traumatic brain injury, hyperthyroidism, severe pain, metabolic disorder, hypoxia, drug poisoning or electrolyte disorder.

13. For the use according to any one of claims 1 to 10, wherein, The diseases or disorders associated with the non-sedated state are selected from the group including the following: anxiety, mental tension, convulsion or insomnia.

14. A pharmaceutical composition, wherein, The pharmaceutical composition comprises the active peptide and / or its functionally equivalent variant according to any one of claims 1-10 and a pharmaceutically acceptable excipient.

15. The pharmaceutical composition according to claim 14, wherein, The pharmaceutical composition comprises one, two or more of other compounds for sedation.

16. A method for sedation or for preventing and / or treating a disease or disorder associated with a non-sedated state, comprising administering to a subject the active peptide as defined in any one of claims 1-10 and / or a functionally equivalent variant thereof, or administering the pharmaceutical composition according to claim 14 or 15.

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