WO2023125112A1 - Composition d'antagoniste et son application, entrant dans la préparation d'un médicament destiné au traitement de troubles du sommeil accompagnés de troubles psychiatriques comorbides - Google Patents

Composition d'antagoniste et son application, entrant dans la préparation d'un médicament destiné au traitement de troubles du sommeil accompagnés de troubles psychiatriques comorbides Download PDF

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WO2023125112A1
WO2023125112A1 PCT/CN2022/140077 CN2022140077W WO2023125112A1 WO 2023125112 A1 WO2023125112 A1 WO 2023125112A1 CN 2022140077 W CN2022140077 W CN 2022140077W WO 2023125112 A1 WO2023125112 A1 WO 2023125112A1
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receptor antagonist
crh
antagonist
combination
structure shown
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PCT/CN2022/140077
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Chinese (zh)
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王立平
曾渝婷
赵炳皓
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中国科学院深圳先进技术研究院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the invention belongs to the technical field of biomedicine, and relates to an antagonist composition and its application in the preparation of medicines for treating sleep disorders and mental diseases.
  • Sleep disturbance is present. This reflects the high correlation between sleep and the development of mental illness. Sleep includes non-rapid eye movement sleep (NREM) and rapid eye movement sleep (rapid eye movement sleep, REM), each with different functions. Changes in REM sleep structure are more common in patients with mental disorders associated with fear disorders such as depression, anxiety and post-traumatic stress disorder. For example, Dieter Riemann et al.
  • NREM non-rapid eye movement sleep
  • REM rapid eye movement sleep
  • Changes in REM sleep structure are more common in patients with mental disorders associated with fear disorders such as depression, anxiety and post-traumatic stress disorder. For example, Dieter Riemann et al.
  • sedatives are also used clinically to treat patients with mental illnesses such as depression/anxiety/post-traumatic stress disorder. It is a more effective treatment to calm the patient down while reducing the symptoms of mental illness program, but sedative drugs are addictive. Adverse effects include addiction problems with continuous use and acute poisoning. Many antidepressants are accompanied by the effect of inhibiting REM sleep and improving depressive symptoms. These drugs reflect the high correlation between the regulation of REM sleep and the improvement of depressive symptoms, but most of the targets of antidepressants in the brain are not Not clear, especially the regulation mechanism of sleep. Due to the poor understanding of the pathogenesis of depression, it is impossible to design antidepressant drugs in a targeted manner.
  • the object of the present invention is to provide an antagonist composition and its application in the preparation of medicines for treating sleep disorders and mental diseases.
  • the present invention provides an antagonist composition, which includes a CRH receptor antagonist and a glutamatergic receptor antagonist.
  • the present invention found for the first time that regulating the activity of corticotropin releasing hormone (CRH) neurons in the subthalamic nucleus or its downstream lateral globus pallidus brain area can change the duration/stability of REM sleep and the degree of fear response, It shows that the subthalamic nucleus and its downstream brain regions are the functional regulatory targets of the comorbidity of sleep disorders and fear disorder-related mental diseases.
  • CHL corticotropin releasing hormone
  • the present invention also found for the first time that CRH neurons in the subthalamic nucleus have a high overlap ratio with glutamatergic neurons, suggesting that such neurons co-release CRH and glutamatergic neurons.
  • the present invention combines CRH receptor antagonists with glutamatergic receptor antagonists to realize the regulation of CRH and glutamate signal transmission in the subthalamic nucleus-lateral pallidus, thereby improving sleep disorders Unusual comorbidity with psychiatric disorders associated with dysregulation of fear emotions.
  • the ratio of the amount of substances of the CRH receptor antagonist to the glutamatergic receptor antagonist is (1-10):(1-10), and the specific values in (1-10) are for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.
  • the CRH receptor antagonists include compounds having the structure shown in formula I, compounds having the structure shown in formula II, compounds having the structure shown in formula III, compounds having the structure shown in formula IV, N-butyl -N-ethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine), NBI30775 , 3-(6-(dimethylamino)-4-methylpyridin-3-yl)-2,5-dimethyl-N,N-dipropylpyrazolo[1,5-A]pyrimidine Any one or a combination of at least two of -7-amine, verteporfin or analamine hydrochloride;
  • the CRH receptor antagonist includes any one of the compounds having the structure shown in formula I, the compound having the structure shown in formula II, the compound having the structure shown in formula III, and the compound having the structure shown in formula IV One or a combination of at least two, such as a combination of a compound having the structure shown in formula I and a compound having the structure shown in formula II, a compound having the structure shown in formula III and a compound having the structure shown in formula IV Combinations of compounds having the above structure, combinations of compounds having the structure represented by formula II and compounds having the structure represented by formula III, etc., other arbitrary combinations are possible.
  • the CRH receptor antagonist includes a compound having the structure shown in formula III, and its name is CP-154526.
  • the glutamate receptor antagonists include N-methyl-D-aspartate receptor antagonists, ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole receptor antagonists , any one or a combination of at least two of kainic acid receptor antagonists or metabotropic glutamate receptor antagonists.
  • the combination of at least two such as the combination of N-methyl-D-aspartate receptor antagonist and kainate receptor antagonist, the combination of kainate receptor antagonist and metabotropic glutamate receptor
  • a combination of kainic acid receptor antagonists, a combination of kainic acid receptor antagonists and an N-methyl-D-aspartate receptor antagonist, etc., and other arbitrary combinations are possible.
  • the glutamate receptor antagonist comprises an N-methyl-D-aspartate receptor antagonist.
  • the N-methyl-D-aspartate receptor antagonists include AP5, AP7, CGP-37849, CPP, Saifutai, amantadine, atomoxetine, dextromethorphan, Any one or a combination of at least two of Zhuoxipine, ketamine, memantine, atiganel, fordine, 7-chlorokynuric acid or TK-40.
  • the combination of the at least two kinds for example, the combination of dextromethorphan and dezrozepine, the combination of ketamine and memantine, the combination of fordinine and 7-chlorokynuric acid, etc., any other combination is acceptable.
  • the ⁇ -amino-3 hydroxy-5-methyl-4-isoxazole receptor antagonist includes any one or at least one of NBQX, AMP397, CNQX, tiampanel, NGX426, MQPX or Kaiocephalin A combination of the two.
  • the kainate receptor antagonist includes any one or a combination of at least two of UBP, tiampanel, CNQX, NS102 or Dasolampanel.
  • the combination of the at least two kinds for example, the combination of UBP and Ticampanel, the combination of Ticampanel and CNQX, the combination of CNQX and NS102, etc., any other combinations are acceptable.
  • Tejapanel and CNQX are not only ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole receptor antagonists, but also kainic acid receptor antagonists.
  • the metabotropic glutamate receptor antagonist includes any one or a combination of at least two of MTEP, Lithium, APICA or EGLU.
  • the combination of the at least two kinds for example, the combination of MTEP and Lithium, the combination of Lithium and APICA, the combination of APICA and EGLU, etc., any other combination can be used.
  • the present invention provides the use of the antagonist composition as described in the first aspect in the preparation of a medicament for treating sleep disorders and mental illnesses.
  • the present invention provides the application of CRH receptor antagonist in the preparation of medicine for treating sleep disorder and mental disease comorbidity.
  • the CRH receptor antagonists include compounds having the structure shown in formula I, compounds having the structure shown in formula II, compounds having the structure shown in formula III, compounds having the structure shown in formula IV, N-butyl -N-ethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine), NBI30775 , 3-(6-(dimethylamino)-4-methylpyridin-3-yl)-2,5-dimethyl-N,N-dipropylpyrazolo[1,5-A]pyrimidine Any one or a combination of at least two of -7-amine, verteporfin or analamine hydrochloride;
  • the CRH receptor antagonist includes any one of the compounds having the structure shown in formula I, the compound having the structure shown in formula II, the compound having the structure shown in formula III, and the compound having the structure shown in formula IV one or a combination of at least two.
  • the CRH receptor antagonist includes a compound having the structure shown in formula III, and its name is CP-154526.
  • the present invention provides the use of a glutamatergic receptor antagonist in the preparation of a medicament for treating sleep disorders and mental illnesses.
  • the glutamate receptor antagonists include N-methyl-D-aspartate receptor antagonists, ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole receptor antagonists , any one or a combination of at least two of kainic acid receptor antagonists or metabotropic glutamate receptor antagonists.
  • the glutamate receptor antagonist comprises an N-methyl-D-aspartate receptor antagonist.
  • the N-methyl-D-aspartate receptor antagonists include AP5, AP7, CGP-37849, CPP, Saifutai, amantadine, atomoxetine, dextromethorphan, Any one or a combination of at least two of Zhuoxipine, ketamine, memantine, atiganel, fordine, 7-chlorokynuric acid or TK-40.
  • the ⁇ -amino-3 hydroxy-5-methyl-4-isoxazole receptor antagonist includes any one or at least one of NBQX, AMP397, CNQX, tiampanel, NGX426, MQPX or Kaiocephalin A combination of the two.
  • the kainate receptor antagonist includes any one or a combination of at least two of UBP, tiampanel, CNQX, NS102 or Dasolampanel;
  • the metabotropic glutamate receptor antagonist includes any one or a combination of at least two of MTEP, Lithium, APICA or EGLU.
  • the mental illness in the present invention includes any one or a combination of at least two of depression, anxiety, bipolar disorder, post-traumatic stress disorder, panic disorder, obsessive-compulsive disorder or autism spectrum disorder.
  • the medicament for treating sleep disorders and psychiatric diseases co-morbidity prepared by the CRH receptor antagonist, glutamatergic receptor antagonist or antagonist composition of the present invention can be used for sleep and psychiatric disease co-morbidity.
  • Diseased animals including humans or non-human primates, rats, mice and the like are also included.
  • the medicament for treating sleep disorders and mental illness comorbidities prepared by the CRH receptor antagonist, glutamatergic receptor antagonist or antagonist composition of the present invention can be administered locally or
  • the purpose of targeted drug delivery is to limit the range of drug diffusion, reduce side effects, and reduce non-specific drug binding.
  • a microcannula can be used for local administration. Specifically, the microcannula is implanted above the globus pallidus on the outside of the subject, and the cannula is combined with a microinjection pump for administration. In addition, it can also be used in combination with a targeted drug delivery system for drug delivery, such as drug release targeting the specific protein binding site of the lateral globus pallidum.
  • the present invention has the following beneficial effects:
  • the present invention found for the first time that regulating the activity of corticotropin releasing hormone (CRH) neurons in the subthalamic nucleus or its downstream lateral globus pallidus brain area can change the duration/stability of REM sleep and the degree of fear response, It shows that the subthalamic nucleus and its downstream brain regions are the functional regulatory targets of the comorbidity of sleep disorders and fear disorder-related mental diseases.
  • CHL corticotropin releasing hormone
  • the present invention also finds for the first time that CRH neurons in the subthalamic nucleus have a high overlap ratio with glutamatergic neurons, suggesting that there is a joint release of CRH and glutamatergic neurons in these neurons, which can be stimulated by optogenetic technology.
  • Stimulation of the subthalamic nucleus-lateral globus pallidum circuit in subjects can increase REM sleep and regulate defensive escape behavior, and administering receptor antagonists to the lateral pallidus through a small cannula can activate CRH neurons in the subthalamic nucleus Then it can basically eliminate the changes of REM sleep and fear response caused by light stimulation.
  • CRH neurons are basically glutamatergic neurons, so CRH and glutamate receptor antagonists are used to regulate the lateral globus pallidus , by weakening or blocking the signal transduction of the subthalamic nucleus-lateral globus pallidus loop, so as to realize the regulation of mental illness symptoms related to abnormal sleep and fear response, it is an effective method to improve sleep disorders and fear disorders.
  • the present invention creatively proposes the application of CRH receptor antagonists and glutamatergic receptor antagonists in the preparation of drugs for the treatment of sleep disorders and mental illnesses. It is also proposed that glutamatergic receptor antagonists be used in combination with CRH receptor antagonists to further improve the regulation of the subthalamic nucleus-lateral globus pallidus loop, and to prepare drugs for the treatment of sleep disorders and mental illnesses .
  • the drug can act on the subthalamic nucleus-the lateral globus pallidus loop through local administration, the scope of action is small, and the target of action is known, so it is safer to use (safety here refers to fewer side effects) , through the joint action of two antagonists, to achieve the regulation of sleep and mental disease co-morbidity, which is also the first composition that can act on the regulation target of sleep and psychiatric disease co-morbidity that the applicant consulted.
  • the present invention does not negate the effects of other psychiatric drugs, but only provides an antagonist composition, which can be used to prepare drugs for the treatment of sleep disorders and psychiatric diseases, so that it can target the drugs used for sleep and psychiatric diseases. In patients, especially those who do not respond to other psychiatric medications.
  • Figure 1 is a schematic diagram of the CRH promoter sequence.
  • Figure 2A is a schematic diagram of chemically inhibited virus injection and electrophysiological function verification.
  • Fig. 2B is a schematic diagram of the test subject's response to natural enemy odor in sleep state.
  • Figure 2C is a graph of the test results of awakening induced by natural enemy odor stimulation in non-REM sleep.
  • Figure 2D is a graph of the test results of awakening induced by natural enemy odor stimulation under rapid eye movement sleep.
  • Figure 2E is a graph showing the test results of the defense response induced by natural enemy odor in the awake state.
  • Figure 2F is a diagram of the test results of defense responses elicited by visual fear stimuli in the awakening state.
  • Figure 2G is a schematic diagram of virus injection and optical fiber implantation in the subthalamic nucleus of a subject.
  • Figure 2H is a graph of the test results of light stimulation-induced awakening under REM sleep.
  • Figure 3A is a schematic diagram of fluorescently labeled virus injection.
  • Figure 3B is a graph showing the overlapping results of Vglut2 probe-labeled cells and virus EYFP-labeled cells.
  • Figure 3C is a projection of virus-labeled glutamatergic neurons in the subthalamic nucleus to the lateral globus pallidus.
  • Fig. 3D is a test result diagram of the overlap between CRH neurons and glutamatergic neurons in the subthalamic nucleus.
  • Figure 4A is a schematic diagram of optogenetic virus and antagonist injection.
  • Fig. 4B is a diagram of the test results of time-induced awakening without natural enemy odor under non-REM sleep.
  • Figure 4C is a graph showing the test results of awakening induced by time without natural enemy odor under rapid eye movement sleep.
  • Figure 4D is a graph of the test results of awakening induced by time with the smell of natural enemies under rapid eye movement sleep.
  • Figure 4E is a graph showing the results of the visual instinctive fear looming test.
  • This example explores the regulatory effect of CRH neurons in the subthalamic nucleus on REM sleep and fear response.
  • AAV9-Crh-Cre and AAV9-DIO-Syn-hM4Di-mCherry were expressed in the subthalamic nucleus of the subject (C57BL6J wild-type mice) through stereotaxic brain region and micro-injection of virus (experimental group).
  • a total of 75 nanoliters were injected after mixing the substance ratio of 1:1); or AAV9-Crh-Cre and AAV9-DIO-Syn-mCherry (control group) (after mixing the two at a substance ratio of 1:1 A total of 75 nL was injected).
  • AAV9-Crh-cre is used to express the Cre enzyme in the neurons expressing CRH in the subject, wherein the CRH promoter sequence was reported by J Chen et al. in 2012 (see Figure 1 for details).
  • the sequence of AAV9-DIO-Syn-hM4Di-mCherry and AAV9-DIO-Syn-mCherry contains a loxp site, which can be recognized by Cre enzyme, and the sequence can be reversed by Cre enzyme, thereby starting the expression of functional protein, so as to achieve Express hM4Di-mCherry (ie, chemoinhibitory receptor hM4Di and red-labeled fluorescent protein mCherry) or express mCherry.
  • Clozapine N Oxide that binds to the chemical inhibitory receptor, it binds to the hM4Di protein to inhibit the CRH neurons of the subthalamic nucleus, while only expressing mCherry but not expressing hM4Di will not produce an inhibitory effect.
  • Fig. 2A upper panel schematic diagram of virus injection, scale bar is 500 ⁇ m).
  • Whole-cell patch-clamp recordings were performed 4 weeks after hM4Di-mCherry virus injection to verify the effect of hM4Di on suppressing neuronal activity (Fig. 2A lower panel).
  • test the subject After confirming that the virus is well expressed and its function is confirmed, test the subject’s response to the odor of natural enemies in the sleeping state (Figure 2B), and the subject implants EEG (electroencephalogram)/EMG (electromyography) to record changes in sleep state , give the natural enemy odor when recognizing NREM or REM sleep respectively, the results are shown in Figure 2C and Figure 2D, the subjects wake up when they feel the natural enemy odor, the latency of awakening (that is, the time from the stimulation of the natural enemy odor to the awakening time interval) NREM was longer, and both mCherry control group and hM4Di were around 40s.
  • the average awakening latency of the mCherry group was about 2s, which indicated that compared with NREM sleep, subjects in REM sleep responded faster to the odor of natural enemies.
  • the hM4Di group was about 10s, indicating that chemical inhibition of CRH neurons prolongs the latency of awakening.
  • the middle graph and the right graph of Fig. 2C/Fig. 2D are the average EEG power density spectra before the natural enemy odor stimulation to the subjects.
  • Figure 2G is a schematic diagram of virus injection and optical fiber implantation in the subthalamic nucleus of a subject.
  • AAV-Crh-Cre and AAV-DIO-EF1a-Arch3.0-EYFP were mixed at a substance ratio of 1:1 and injected with a total of 75 nanoliters as the experimental group;
  • AAV-Crh-Cre and AAV-DIO- EF1a-EYFP was mixed at a substance ratio of 1:1 and injected with a total of 75 nanoliters as a control group.
  • the AAV-Crh-Cre virus can be used to express the Cre enzyme in the CRH-expressing neurons of the subthalamic nucleus, and Arch3.
  • Outflow to achieve the effect of neuron inhibition, can be used for real-time yellow light stimulation to cause neuron inhibition, and the combination of the two can achieve the effect of light inhibition on CRH neurons in the subthalamic nucleus.
  • an optical fiber was implanted 0.1 mm above the virus injection area of the subthalamic nucleus for 4 weeks to deliver yellow light stimulation, and EEG/EMG was implanted to record the state of sleep and wakefulness. Photostimulation was initiated at the onset of REM sleep and terminated at the end of REM sleep. It was found that after expressing Arch protein, light stimulation significantly reduced the duration of REM sleep, and from the EEG power map (Fig. Increased, indicating that photoinhibition of CRH neurons affects the stability of REM sleep. All data are expressed as mean ⁇ SEM.
  • this example confirms the regulatory effect of CRH neurons in the subthalamic nucleus on REM sleep and fear response.
  • the present invention confirms the regulating effect of the CRH neurons of the subthalamic nucleus on REM sleep and fear response through Example 1, the CRH neuron types of the subthalamic nucleus are further analyzed. This example explores the overlap between CRH neurons and glutamatergic neurons in the subthalamic nucleus.
  • the primer sequences used in the present invention are all from Allen Brain Atlas:
  • the slc17a6/Vglut2 probe primer sequence is: CCAAATCTTACGGTGCTACCTC/TAGCCATCTTTCCTGTTCCACT (SEQ ID NO 1).
  • CRH probe primer sequence is: TAGAGCCTGTCTTGTCTGTGG/AGCATGGGCAATACAAATAACGCT (SEQ ID NO 2).
  • This example explores the effects of administering CRH receptor antagonists on sleep and fear responses.
  • the CRH antagonist group was used as the experimental group, and the DMSO solvent group was used as the control group.
  • the CRH antagonist is selected from CP154526, which can bind to CRH receptor type 1, thereby competitively blocking the binding of CRH transmitters.
  • Figure 4E is the results of the visual instinct fear looming test, as shown in the figure, compared with the control group DMSO, the CRH antagonist group significantly prolongs the initiation of defense response time, prolongs the time to return to the safe area, and shortens the time to stay in the safe area, indicating that CRH antagonists attenuated defense responses evoked by visceral fear stimuli in waking conditions.
  • this example proves that CRH antagonists can weaken the response to natural enemy stimuli during REM sleep, and attenuate the defense response induced by visual instinctive fear stimuli.
  • CRH antagonists can weaken the response to natural enemy stimuli during REM sleep, and attenuate the defense response induced by visual instinctive fear stimuli.
  • Drugs are used in combination to improve the regulation of the subthalamic nucleus-lateral globus pallidus loop, and are used to prepare drugs for treating sleep disorders and mental diseases.
  • the present invention illustrates an antagonist composition of the present invention and its application in the preparation of drugs for the treatment of sleep disorders and mental illness comorbidities through the above examples, but the present invention is not limited to the above examples , that is, it does not mean that the present invention can only be implemented depending on the above-mentioned embodiments.
  • Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.

Abstract

L'invention concerne une composition d'antagoniste et son application, entrant dans la préparation d'un médicament destiné au traitement de troubles du sommeil accompagnés de troubles psychiatriques comorbides ; ladite composition d'antagoniste comprend un antagoniste du récepteur CRH et un antagoniste du récepteur de l'acide glutamique. Il a été découvert pour la première fois que la régulation et la commande de l'activité neuronale d'un neurone hormonal de libération d'hormone adrénocorticotrope de noyau sous-thalamique ou d'une région aval de globus pallidus externe de ce dernier peuvent modifier la durée/la stabilité de sommeil paradoxal et le degré de réaction de peur, indiquant ainsi que le noyau sous-thalamique et la région cérébrale aval de ce dernier sont des cibles de régulation et de commande fonctionnelles chez les patients souffrant de maladies mentales associées à un trouble du sommeil et à un déséquilibre de la peur. Il a également été découvert pour la première fois que le neurone CRH du noyau sous-thalamique et le neurone de l'acide glutamique ont un rapport de coïncidence élevé. Sur la base des découvertes ci-dessus, l'antagoniste du récepteur CRH est combiné avec l'antagoniste du récepteur de l'acide glutamique pour réguler et commander la transmission du signal CRH et de l'acide glutamique du globus pallidus externe du noyau sous-thalamique, de sorte que le trouble du sommeil et les co-morbidités anormales de troubles psychiatriques liés au déséquilibre du sentiment de peur sont améliorés.
PCT/CN2022/140077 2021-12-29 2022-12-19 Composition d'antagoniste et son application, entrant dans la préparation d'un médicament destiné au traitement de troubles du sommeil accompagnés de troubles psychiatriques comorbides WO2023125112A1 (fr)

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