WO2013176220A1 - Régulation du rythme circadien - Google Patents

Régulation du rythme circadien Download PDF

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WO2013176220A1
WO2013176220A1 PCT/JP2013/064376 JP2013064376W WO2013176220A1 WO 2013176220 A1 WO2013176220 A1 WO 2013176220A1 JP 2013064376 W JP2013064376 W JP 2013064376W WO 2013176220 A1 WO2013176220 A1 WO 2013176220A1
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circadian rhythm
inhibitor
rhythm
vasopressin receptors
item
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Japanese (ja)
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均 岡村
賀章 山口
辻本　豪三
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国立大学法人京都大学
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a circadian rhythm adjusting agent, a prophylactic or therapeutic agent for a disease or condition caused by disturbance of the circadian rhythm, a circadian rhythm adjusting composition and preparation, and a method for screening a substance for preparing a circadian rhythm (circadian rhythm). , Use for circadian rhythm adjustment, circadian rhythm adjustment method.
  • clock genes The suprachiasmatic nucleussup (SCN) in the diencephalon hypothalamus is called the “master clock” because it has a function to control peripheral clocks in cells throughout the body. It works as the center of rhythm formation.
  • SCN suprachiasmatic nucleussup
  • a series of biological phenomena controlled by clock genes is called “circadian rhythm”.
  • rhythms examples include sleep / wake rhythms, appetite, libido, body blood pressure and body temperature rhythms, endocrine rhythms such as corticosteroids, melatonin and growth hormone secretion, immune system rhythms, autonomy Neural rhythms are known.
  • the circadian rhythm is set so that it can synchronize with the environmental period of 24 hours such as the light and dark cycle that occurs with the rotation of the earth, that is, the light and dark cycle.
  • Sexual animals are easier to act in the daytime. For this reason, humans are usually most productive in the daytime.
  • it may be required to act in an unusual time zone. For example, a traveler who travels a long distance in a short time by an aircraft experiences a phase shift between the daytime and nighttime at the departure and arrival points, causing the so-called “jet-lag” syndrome.
  • jet lag syndrome sleep / wake rhythm is disturbed and attention and concentration are reduced until the circadian rhythm is gradually adjusted to the arrival time zone.
  • the various rhythms described above may be disturbed, resulting in temporary physical insufficiency.
  • shift workers who circulate between morning and evening, evening to midnight, and from midnight to early morning, etc., physical dysfunction due to temporary circadian rhythm disturbance occurred, and as a result , It may be difficult to adjust to shift to work shift.
  • the most common symptom among shift workers is sleep disturbance, which promotes general malaise and fatigue.
  • the night work itself is a physical activity in a state where the autonomic nerve, metabolic rhythm, and endocrine rhythm are lowered, so that it is easy to feel general fatigue and fatigue.
  • the time and frequency of meals tend to be irregular, the burden on the gastrointestinal tract and endocrine organs is large, and autonomic nerve malfunction occurs, so various digestive symptoms are likely to occur.
  • Non-patent Document 1 In shift workers, plasma triglycerides and cholesterol have been reported to increase (Non-patent Document 1). In day shift workers, there is a large difference in blood pressure between sleep and awake, and shift work It has been reported that the difference is small among non-patents (Non Patent Literature 2).
  • Non-patent Document 3 In elderly people, a decrease in the synthesis of an endogenous factor (for example, melatonin) for forming a circadian rhythm is recognized, and there is a concern about a decrease in the maintenance power of the circadian rhythm (Non-patent Document 3).
  • an endogenous factor for example, melatonin
  • nerve cells expressing AVP (arginine vasopressin) and VIP (vasoactive intestinal polypeptide) in the suprachiasmatic nucleus (SCN) transmit clock signals by releasing these peptides into the brain. It is considered. It has been reported that elderly people have less sharpness of the circadian rhythm related to the expression of the number of AVP-expressing neurons in the day and night compared to young people (Non-patent Document 4).
  • Non-Patent Documents 5 and 6 Young people with irregular lives and workers who have to work long hours over night are often triggered by irregular bedtime and mealtime, resulting in a shift in the external environment and circadian rhythm. , You may feel sick. A study of healthy young subjects simulating shift work showed that after eating a standard meal, blood glucose levels, insulin and lipid levels were affected by changes in life rhythm, and insulin resistance and lipid levels It has been reported that metabolic changes occur (Non-Patent Documents 5 and 6).
  • melatonin also has actions other than circadian rhythm adjustment, such as hypnotic action and endocrine action (Non-patent Document 7), and if taken for the purpose of circadian rhythm adjustment, they become side effects. . Similar side effects remain for melatonin derivatives and serotonin, 5-hydroxytryptophan, and tryptophan, which are melatonin precursors that are converted to melatonin in the body. In particular, when serotonin is taken orally, oral absorbability is poor, and adverse effects on the digestive system and circulatory system have been reported (Non-patent Documents 8 and 9).
  • the object of the present invention is to provide a technique for preventing, improving and controlling various diseases, conditions and symptoms caused by disturbance of circadian rhythm.
  • the present invention relates to the following circadian rhythm adjusting agents, preventive or therapeutic agents for diseases or conditions caused by disturbance of circadian rhythms, circadian rhythm adjusting compositions and preparations, substances for preparing circadian rhythms (circadian rhythms) It provides screening methods, use for circadian rhythm adjustment, and circadian rhythm adjustment methods.
  • Item 1 A circadian rhythm regulator comprising as an active ingredient an inhibitor that inhibits vasopressin receptors V1a and V1b.
  • a preventive or therapeutic agent for a disease or condition caused by disturbance of circadian rhythm comprising an inhibitor that inhibits vasopressin receptors V1a and V1b as active ingredients.
  • circadian rhythm disturbances Diseases or conditions resulting from circadian rhythm disturbances include sleep disorders, insomnia, delayed sleep phase syndrome, fatigue, jet lag, sleep phase regression syndrome, autonomic ataxia, fatigue, general malaise, metabolic rhythm disturbances, Item 3.
  • Item 4. A circadian rhythm adjusting composition comprising an inhibitor of V1a and V1b which are vasopressin receptors and an excipient.
  • Item 5 Item 5.
  • the composition according to Item 4 which is a pharmaceutical composition or a food composition.
  • a circadian rhythm-regulating preparation comprising inhibitors of V1a and V1b, which are vasopressin receptors.
  • Item 7. The preparation according to Item 6, which is a granule, powder, tablet, chewable tablet, capsule, syrup, drink, suspension or injection.
  • Item 8. A method for screening a circadian rhythm modulator, which comprises detecting inhibitors of V1a and V1b, which are vasopressin receptors.
  • Item 9. Use of an inhibitor of vasopressin receptors V1a and V1b for circadian rhythm adjustment.
  • Item 10. A circadian rhythm adjustment method comprising administering an inhibitor of vasopressin receptors V1a and V1b to a mammal.
  • Adjustment of circadian rhythm is sleep disorder, insomnia, delayed sleep syndrome, fatigue, jet lag, sleep phase regression syndrome, autonomic ataxia, fatigue, general malaise, metabolic rhythm disturbance, endocrine disorder, sleepiness, anorexia, Item 3.
  • the circadian rhythm modifier according to Item 1 which is any improvement selected from the group consisting of poor physical condition, decreased concentration or motivation, depression, anxiety, and gastrointestinal dysfunction,
  • the circadian rhythm adjustment composition according to claim 8 the preparation according to item 7, the screening method according to item 8, the use according to item 9, or the method according to item 10.
  • the circadian rhythm modifier according to Item 1 the prophylactic or therapeutic agent according to Item 2 or 3, wherein the inhibitor of V1a and V1b inhibits vasopressin receptors V1a and V1b and does not inhibit V2, Item 4 Item 11.
  • the circadian rhythm adjustment composition according to any one of items 6 to 6, the preparation according to item 7, the screening method according to item 8, the use according to item 9, or the method according to item 10.
  • Item 13 Item 13.
  • the circadian rhythm regulator according to Item 1 the prophylactic or therapeutic agent according to Item 2 or 3, wherein the V1a and V1b inhibitors are antagonists of V1a and V1b which are vasopressin receptors, Item 11.
  • Item 14 The circadian rhythm adjusting agent according to Item 1, the prophylactic or therapeutic agent according to Item 2 or 3, wherein the V1a and V1b inhibitor is a combination of an inhibitor of V1a and an inhibitor of V1b, Item 11.
  • the circadian rhythm regulator according to Item 1 the preventive or therapeutic agent according to Item 2 or 3, wherein the inhibitor of V1a and V1b is at least one substance that inhibits both V1a and V1b, Item 10.
  • sleep disorders insomnia, sleep phase delay syndrome, fatigueability, jet lag, sleep phase regression syndrome, autonomic dysfunction, fatigue, general malaise, metabolic rhythm disturbance, endocrine disturbances Disorders caused by disturbances in circadian rhythm, such as disability, sleepiness, loss of appetite, poor physical condition, poor concentration or motivation, depression, anxiety, gastrointestinal dysfunction (diarrhea, constipation, stomach upset, indigestion, etc.)
  • the condition can be improved.
  • WT and V1a -/- V1b -/- behavior when 8 hours phase advance and release to DD one day later (pyroelectric infrared sensor, fluorescent lamp 200 lux)
  • WT and V1a- / - V1b - / - both n 10
  • the phase response of behavioral rhythm to light was also verified.
  • Fig. 2 a Changes in the expression of clock genes (Per1, Per2, Bmal1, Dbp) mRNA in the suprachiasmatic nucleus during the 8-hour phase advance in SCN (two points for each point, the line connects the average value).
  • b Transition of peak time of clock gene at 8 hour phase shift. The size of the dot diameter indicates the amplitude of the clock gene.
  • the arrow means V1a-/-V1b-/-. Note that in the suprachiasmatic nucleus, the gene amplitude decreases for 7-8 days, until the 8-hour phase is completely shifted.
  • Fig. 3 a Changes in the expression of clock genes (Per1, Per2, Bmal1, Dbp) mRNA in the suprachiasmatic nucleus during the 8-hour phase advance in SCN (two points for each point, the line connects the average value).
  • b Transition of peak time of clock gene at 8 hour phase shift. The size of the dot diameter indicates the amplitude of the clock gene.
  • a Representative behavioral rhythms of the control group and the antagonist 2.5mM administration group.
  • b Transition of action start phase after 8-hour phase advance in each group.
  • c PS50 value of the phase displacement of each group (date and time when the phase displacement was completed by 50%).
  • rhythm adjustment composition As a subject to which the circadian rhythm adjustment composition according to the present invention is applied, 1) Patients with an acute syndrome of circadian rhythm sleep disorder, such as those who are at risk of circadian rhythm disorder, that is, shift workers, night / night workers, overseas travelers, etc. 2) Patients with chronic syndrome of circadian rhythm sleep disorder such as delayed phase sleep syndrome 3) Elderly people who are prone to circadian rhythm disorders 4) Those who fall into circadian rhythm disorders due to irregular living behaviors, especially young people and long-time workers. 5) A person whose circadian rhythm is desynchronized due to blindness can be assumed, but is not limited thereto.
  • V1a and V1b are SCN vasopressin receptors, the nucleotide sequence and amino acid sequence of which are disclosed in the database, and the human V1a accession number is gene: NM_000706 and protein: NP_000697.
  • the accession number of human V1b is gene: NM_000707, protein: NP_000698.
  • Inhibitors of V1a and V1b are antagonists of these receptors (antagonists; may be competitive inhibitors or noncompetitive inhibitors), V1a and V1b expression inhibitors, V1a and V1b receptors Examples include protein expression inhibitory substances, function inhibitory substances, and information transmission inhibitory substances that are coupled to the body. These inhibitors may be low-molecular compounds such as drugs, proteins such as antibodies, nucleic acid substances such as siRNA, shRNA and miRNA, aptamers and the like.
  • the food itself or a processed food such as a fermented food, a part of an animal, a plant, a microorganism, or an extract thereof, a plurality of components such as a culture, etc. It may be a composition having
  • the “inhibitor of V1a and V1b” used in the present invention may be a substance that inhibits both V1a and V1b with a single compound, and one or more substances that inhibit both V1a and V1b may be used. Can be mixed and used.
  • a combination (composition) of at least one V1a inhibitor and at least one V1b inhibitor can be used as the “inhibitor of V1a and V1b”.
  • the inhibitors of V1a and V1b and the screening methods thereof have been studied for a long time, and the present invention can use these known inhibitors and inhibitor screening methods as screening methods for circadian rhythm regulating substances.
  • dPenTyr As inhibitors of V1a and / or V1b, dPenTyr (Me) AVP (deamino-Pen, O-Me-Tyr, Arg] -vasopressin), PhAcALVP ([phenylacetyl, O-Me-D-Try, Arg, Lys) ] -Vasopressinamide), d (CH2) 5Tyr (Me) AVP ([ ⁇ -mercapto- ⁇ , ⁇ -cyclopentamethylenepropionyl, O-Me-Tyr, Arg] -vasopressin), WO99 / 37637, WO98 / 39325, WO95 / 34540, WO95 / 06035, WO94 / 04525, WO94 / 01183, WO94 / 01409, JP2000-351768, JP9-221475, JP08-301848, JP08-231512, JP08-19
  • both V1a and V1b are inhibited to adjust the circadian rhythm.
  • V1a and V1b may be inhibited to the same extent, one being strongly inhibited and the other being inhibited more weakly.
  • the active ingredient of the present invention may be a single substance that inhibits both V1a and V1b, or a combination of an inhibitor of V1a and an inhibitor of V1b may be used as an active ingredient.
  • an inhibitor of V1a and an inhibitor of V1b are used as active ingredients in combination, these may be administered / ingested simultaneously, or separately / administered, and V1a and V1b may be simultaneously inhibited for a certain period of time.
  • V1a and V1b double knockout mice have been demonstrated to have lost their time difference, and dose dependently administered V1a and V1b antagonist cocktail (OPC-21268 / SSR149415).
  • a compound or composition that reduces both the time difference readjustment days and inhibits both V1a and V1b is effective in reducing or eliminating the time difference.
  • the circadian rhythm can be re-synchronized with the time difference of the day, and the circadian rhythm adjusting composition of the present invention can be used to adjust the circadian rhythm. It is extremely effective. Even if V1a and V1b are simultaneously suppressed, the clock gene oscillation mechanism is normal. In addition, when V1a and V1b are suppressed simultaneously, the body temperature rhythm also synchronizes quickly.
  • the shift worker tries to adapt his / her physical condition to the working hours by moving the sleeping hours around the working hours.
  • the composition, preventive agent or therapeutic agent, preparation, etc. of the present invention are ingested, the biological rhythm returns to normal in a shorter period of time, and the time of ingestion includes the day of shift work such as night shift or the next day, but is not limited thereto. Not. Nurses, doctors, police officers, firefighters, convenience stores, supermarkets, etc.
  • the composition of the present invention, the preventive agent or the therapeutic agent, and the preparation for the elderly, those with irregular daily activities, the elderly who are prone to circadian rhythm disorders, and those whose circadian rhythm is desynchronized due to blindness, etc. Etc. can reduce the disturbance of biological rhythm.
  • Diseases or conditions caused by circadian rhythm disturbances include sleep disorders, insomnia, delayed sleep phase syndrome, fatigue, jet lag, sleep phase regression syndrome, autonomic ataxia, fatigue, general malaise, metabolic rhythm disturbance Endocrine disorders, drowsiness, loss of appetite, poor physical condition, decreased concentration or motivation, depression, anxiety, dysfunction of the gastrointestinal tract, etc., and the composition, preventive agent, therapeutic agent or preparation of the present invention include: It is effective for these diseases and conditions.
  • Examples of the preparation of the present invention include uncoated tablets, film-coated tablets, dragees, granules, powders, tablets, capsules (including both hard capsules and soft capsules), chewable types, syrup types, drink types, injections, and the like. I can give you. In order to produce these dosage forms, various preparation-producing substances such as excipients, disintegrants, binders, lubricants, flavors, sweeteners and the like can be used.
  • the circadian rhythm adjusting composition of the present invention can also be added to food.
  • the form of the food may be solid, semi-solid or liquid.
  • frozen confectionery such as Western confectionery, Japanese confectionery, snack confectionery, ice cream, ice milk, etc.
  • beverages for example, soft drinks, carbonated drinks (cider, ramune, etc.), condiment drinks, alcoholic drinks, powdered juices, etc.
  • dairy products Milk, yogurt, ice cream, butter, margarine, cheese, whipped cream, etc.
  • ice confectionery, confectionery anko, yokan, bun, chocolate, gum, jelly, agar, apricot tofu, cake, castella, cookies, rice crackers, snacks, etc.
  • the circadian rhythm adjustment composition of the present invention comprises so-called health foods, functional foods, dietary supplements (for example, block or liquid), supplements, foods for specified health use, foods for sick people and foods for sick people (welfares) It is good also as a food for the elderly (Ministry of Health, Labor and Welfare, a kind of special-purpose food).
  • the food may have any property such as a block shape, a gel shape, a paste shape, a liquid, and a solution.
  • the circadian rhythm adjusting composition of the present invention does not require any special process to be added to the food, and is added with the raw material at the beginning of the food production process, added during the production process, or at the end of the production process. Add to.
  • a normal method such as mixing, kneading, dissolution, dipping, spraying, spraying, and application is selected according to the type and properties of the food.
  • the food of the present invention can be prepared according to methods known to those skilled in the art.
  • the circadian rhythm adjustment composition of the present invention can adjust the rhythm depending on the intake amount, and can adjust the rhythm by changing the intake amount or the timing of intake depending on the degree of modulation of the rhythm. it can.
  • the circadian rhythm adjusting composition of the present invention can also be administered as a medicine.
  • the form of administration of the drug is not particularly limited, and can be administered orally or parenterally to humans or non-human mammals depending on the type of active ingredient, formulation form, and the like.
  • an active ingredient that is a V1a and V1b inhibitor may be used as it is, but usually one or two or more pharmaceutically acceptable substances are usually used for the above-mentioned substance that is an active ingredient. It is desirable to provide a pharmaceutical preparation in a form that can be used by those skilled in the art by adding carriers, excipients, diluents, and the like.
  • Examples of the preparation as a dosage unit suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, liquids, syrups, etc.
  • dosage units suitable for parenteral administration examples include injections for subcutaneous, intravenous, or intramuscular injection, drops, suppositories, inhalants, transdermal absorption agents, transmucosal absorption agents, patches, and the like.
  • Carriers, excipients, and diluents include, for example, disintegrants or disintegrants, binders, lubricants, coating agents, dyes, diluents, bases, solubilizers or solubilizers, isotonic agents, A pH adjuster, a stabilizer, a propellant, an adhesive, etc. can be mentioned.
  • These pharmaceutical additives are widely used by those skilled in the art, and it goes without saying that appropriate pharmaceutical additives can be selected depending on the pharmaceutical form.
  • the dosage and administration period of the medicament of the present invention are not particularly limited, but are appropriately determined according to the type of active ingredient, dosage form, degree of tolerance formation, administration purpose such as prophylactic or therapeutic administration, patient age, weight, etc. Just choose.
  • the active ingredient V1a and / or V1b inhibitor can be administered 1 to 4 times per day at a dose of about 0.01 to 1000 mg per day, preferably about 0.1 to 500 mg per day.
  • wild-type mice (WT, V1a + / + V1b + / + mice) were C57BL / 6 male mice aged 7 to 20 weeks, and V1a ⁇ / ⁇ V1b ⁇ / ⁇ mice (V1a and V1b (A double knockout mouse) was prepared by mating the following V1a ⁇ / ⁇ mice and V1b ⁇ / ⁇ mice.
  • V1a -/- mouse V1a vasopressin receptors maintain normal blood pressure by regulating circulating blood volume and baroreflex sensitivity, Proc Natl Acad Sci USA, 103, 7807-7812, 2006 V1b -/- mice, The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions, J Clin Invest, 113, 302-309, 2004
  • Example 1 WT when jet-lag is performed for 8 hours (phase is advanced after 14 days of phase advance: body movement is detected by pyroelectric infrared sensor: fluorescent lamp 200 lux 12 hours light / 12 hours dark cycle)
  • the behavior of V1a-/-V1b-/- was observed.
  • a representative example is shown in FIG.
  • the action of V1a-/-V1b-/-can respond to phase advance or retreat quickly in almost one day, but it is clear that WT takes time to resolve the time difference and requires a period of at least several days became.
  • FIG. 1f shows that V1b ⁇ / ⁇ is large.
  • Example 2 The transition of the expression of the clock gene (Per1, Per2, Bmal1, Dbp) mRNA in the suprachiasmatic nucleus during the 8-hour phase advance in SCN (two points for each point, the line connecting the average values) is shown in FIG.
  • the transition of the peak time of the clock gene during the 8-hour phase shift is shown in FIG. 2b.
  • the size of the dot diameter indicates the amplitude of the clock gene. In the suprachiasmatic nucleus, it is noteworthy that the gene amplitude decreases for 7-8 days, until the 8 hour phase is completely shifted.
  • Example 3 Change in rhythm of WT and V1a ⁇ / ⁇ V1b ⁇ / ⁇ clock genes (Per1, Per2, Bmal1, Dbp) rhythms when the phase is advanced for 8 hours in the liver (connect the average value of each point with a line) As shown in FIG. Moreover, the transition of the peak time of the clock gene at the time of 8-hour phase advance is shown in FIG. In FIG. 3b, the size of the dot diameter indicates the amplitude of the clock gene. It became clear that the amplitude of the liver hardly changed even when the phase was shifted.
  • FIG. 3c The transition of the body temperature rhythm of WT and V1a ⁇ / ⁇ V1b ⁇ / ⁇ when the phase is advanced for 8 hours is shown in FIG. 3c.
  • a thermometer was placed in the abdominal cavity and measured continuously.
  • Figure 3d shows the transition of body temperature peak time during 8-hour phase advance.
  • V1a -/- V1b -/- can not only express the clock gene in the liver, but also the rhythm of body temperature can be quickly adapted to phase advance or phase backward, resulting from disturbance of circadian rhythm It has been proved that it is effective in improving the disease or condition.
  • FIG. 4a shows typical behavior rhythms of the control group and the antagonist 2.5mM administration group
  • FIG. 4b shows the transition of the behavior start phase after the 8-hour phase advance in each group.
  • FIG. 4c shows the PS50 value of the phase displacement of each group (date and time when the phase displacement is 50% completed).
  • V1a and V1b antagonist cocktail (OPC-21268 / SSR149415) reduced the time difference readjustment in a dose-dependent manner, and compounds, formulations or compositions that inhibit both V1a and V1b Proven to be effective in disappearance.

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Abstract

La présente invention concerne un agent de régulation du rythme circadien qui comprend un inhibiteur apte à inhiber les récepteurs de vasopressine V1a et V1b en tant que principe actif.
PCT/JP2013/064376 2012-05-25 2013-05-23 Régulation du rythme circadien WO2013176220A1 (fr)

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WO2015024819A1 (fr) * 2013-08-19 2015-02-26 F. Hoffmann-La Roche Ag Antagonistes de v1a pour traiter des troubles du sommeil impliquant un décalage de phase
WO2023088996A1 (fr) 2021-11-19 2023-05-25 F. Hoffmann-La Roche Ag Synthèse de 2'-(7,7-diméthyl-1'h,7h-spiro[furo[3,4-b]pyridine-5,4'-pipéridin]-1'-yl)-1,3-dihydro-4'h-spiro[indène-2,5'-[1,3]oxazol]-4'-one, et formes cristallines de celle-ci

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015024819A1 (fr) * 2013-08-19 2015-02-26 F. Hoffmann-La Roche Ag Antagonistes de v1a pour traiter des troubles du sommeil impliquant un décalage de phase
JP2016528266A (ja) * 2013-08-19 2016-09-15 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ 位相変位睡眠障害を処置するためのＶ１ａアンタゴニスト
US10265327B2 (en) 2013-08-19 2019-04-23 Hoffmann-La Roche Inc. V1A antagonists to treat phase shift sleep disorders
WO2023088996A1 (fr) 2021-11-19 2023-05-25 F. Hoffmann-La Roche Ag Synthèse de 2'-(7,7-diméthyl-1'h,7h-spiro[furo[3,4-b]pyridine-5,4'-pipéridin]-1'-yl)-1,3-dihydro-4'h-spiro[indène-2,5'-[1,3]oxazol]-4'-one, et formes cristallines de celle-ci

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