WO2012139529A1 - Inhibiteur de d-acide aminé oxydase pour la prévention et/ou l'inversion de la tolérance aux osopioïdes - Google Patents

Inhibiteur de d-acide aminé oxydase pour la prévention et/ou l'inversion de la tolérance aux osopioïdes Download PDF

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WO2012139529A1
WO2012139529A1 PCT/CN2012/074062 CN2012074062W WO2012139529A1 WO 2012139529 A1 WO2012139529 A1 WO 2012139529A1 CN 2012074062 W CN2012074062 W CN 2012074062W WO 2012139529 A1 WO2012139529 A1 WO 2012139529A1
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pain
opioid
morphine
acid oxidase
tolerance
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Chinese (zh)
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王永祥
龚念
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Wang Yongxiang
Gong Nian
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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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/407—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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • Acid oxidase inhibitors prevent and/or reverse opioid tolerance
  • the opening relates to the prevention and/or reversal of opioid tolerance.
  • a D-J ⁇ acid oxidase inhibitor for preventing and/or reversing opioid tolerance and a method for preventing and/or reversing opioid tolerance using a D-amino acid oxidase inhibitor are provided, and A method of preventing and/or treating pain using D-acid oxidase, and a method of identifying a compound for preventing and/or reversing opioid tolerance.
  • Opioid agonists also known as opioid agonists, opioids, opioids, and opioids
  • morphine are a class of narcotic analgesics that are used over long periods of time when relatively high doses are used or although doses are low. It produces a strong drug tolerance, which leads to a decrease in the analgesic effect of the analgesic.
  • an anesthetic analgesic should be used in an increased dose to achieve the desired analgesic effect.
  • the increased dose of this narcotic analgesic leading to different side effects, serious toxicity to humans, and serious clinical problems such as serious clinical problems and drug abuse, is urgently needed for development, prevention, intervention and resistance. Broken opioid-tolerant agents.
  • Pain is one of the most common symptoms in the clinic. Many diseases or conditions have pain symptoms and seriously affect the quality of life of patients. Treatment of pain has become one of the most considered factors in health care and disease treatment. Therefore, pain has received more and more attention from the medical community. 2000-2010 has been called the pain era. Pain is an unpleasant sensation and emotional experience associated with acute or potential tissue damage that prompts people to avoid the devastating condition, thereby protecting the body and avoiding further damage. Most of the pain disappears immediately after the pain stimulus is removed, but sometimes the pain persists even though the stimulus has been eliminated and the body has recovered significantly. In addition, sometimes pain occurs despite the absence of any irritation, destruction or disease.
  • Peripheral ectopic discharge and central sensitization are currently recognized as the main mechanisms of chronic pain including neurogenic pain and tumor pain formation (Basbaum et al. Cell 139: 267- 284, 2009).
  • the incidence of chronic pain is high, accounting for about 10% of the total population, and increases with age and prolonged prolonged disease (eg, the incidence rate is over 13% over 55 years old, and 8% in the early diagnosis of diabetes. Diagnostics up to 50% after 25 years).
  • Pain (such as various forms of chronic pain, including cancer pain, neuropathic pain, etc.) is inadequately available in wards, intensive care units (ICUs), emergency departments, and the like. Pain can be treated with drugs, psychotherapy, physiotherapy, and traditional medical therapies.
  • the current clinical treatment of chronic pain mainly includes tricyclic antidepressants such as amitriptyline, antiepileptic drugs such as gabapentin and pregabalin, local anesthetics such as lidocaine, opioids (such as Dihydromorphone, fentanyl and buprenorphine), adrenergic receptor antagonists such as clonidine, and 5-HT reuptake inhibitors such as duloxetine and ziconotide.
  • analgesic ladder therapy that is, mild cancer pain, non-steroidal anti-inflammatory analgesics represented by aspirin and indomethacin, moderate cancer Sexual pain uses weak opioid moderate analgesics such as tramadol, codeine, and oxycodone.
  • an anesthetic with strong opioid receptor agonists such as morphine and chilling is required.
  • Opioid receptor agonists while effectively controlling severe pain, bring serious clinical problems of drug tolerance and serious social problems such as drug abuse on an international scale.
  • the high-dose anesthetic drugs used to treat severe pain have significant side effects such as inhibition of breathing, vomiting, and visceral smooth muscle spasm, and the side effects of visceral smooth muscle spasm must be improved by using atropine and other drugs, otherwise it will become Aggravating the cause of common visceral pain such as biliary colic and renal colic, which is one of the reasons why the analgesic effect lasts for a short time.
  • Analgesics are commonly used medical drugs to suppress or relieve acute pain. Analgesics are usually classified into narcotic and non-narcotic. Clinically, narcotic analgesics are used to treat acute pain in patients with advanced cancer because they have excellent analgesic effects on visceral pain. However, when an anesthetic analgesic is administered at a relatively high dose or although it is administered at a low dose for a long period of time, it may result in a habitual administration of the analgesic and a desire for an analgesic.
  • an anesthetic analgesic should be used in an increased dose to achieve the desired analgesic effect.
  • the increase in the dose of this narcotic analgesic causes different side effects and thus has Severe toxicity.
  • opioid agonists are known to be the most commonly used analgesic analgesics, of which morphine, fentanyl and the like are currently used as opioid agonist analgesics, such as morphine. 80% share.
  • opioid agonists such as morphine may result in a gradual decrease in analgesic effects and ultimately lead to tolerance to opioid analgesia.
  • opioid agonists such as morphine in the clinical field is limited. Therefore, in order to utilize an opioid agonist such as morphine as an analgesic, it is very important to maintain the initial analgesic effect of the opioid agonist without reducing the analgesic effect upon repeated use. This object can be achieved by inhibiting the development of tolerance to opioid agonists.
  • Opioid tolerance refers to the prolonged or even disappearance of drug analgesic effects after prolonged use of opioids (opioid agonists), or the need to gradually increase opioids if the same degree of analgesic effect is required.
  • the dose in addition to showing a decrease in the analgesic effect of the drug, and an increase in the dose required for the drug, can also lead to more severe hyperalgesia.
  • opioid tolerance is a complex biochemical process, and a large number of experimental studies have confirmed that opioid receptor desensitization and endocytosis (Gainetdinov et al., Ann Rev Neurosci 27: 107-144, 2004) Post-receptor signal transduction (Raval et al., J Neurosci 27: 107-144, 2004) and transcription factors that cause changes in neuronal plasticity (Miyabe and Miletic, Neurosci Lett 38: 80-85, 2005) are involved. Formation of opioid tolerance.
  • D-amino acid oxidase inhibitors including CBIO, AS057278 and sodium benzoate, are capable of preventing and/or reversing the tolerance produced by opioid agonist treatment.
  • the inventors have also unexpectedly found that, contrary to the prediction according to the prior art, the acid oxidase inhibitor itself is capable of significantly preventing and/or pain.
  • the present disclosure provides a method of preventing and/or reversing opioid tolerance comprising administering an effective amount of a D-amino acid oxidase inhibitor to a subject in need thereof.
  • the method is for preventing and/or treating a condition which is reduced in therapeutic efficacy due to opioid tolerance, the condition being capable of achieving prevention and/or opioid tolerance by inhibiting D-amino acid oxidase Get prevented and / or treated.
  • the condition can be pain, including but not limited to acute and/or chronic pain, especially chronic pain, such as cancer pain.
  • the condition that is reduced in therapeutic efficacy due to opioid tolerance is selected from the group consisting of chronic pain, cancer pain, neuropathic pain, chronic low back pain, headache, migraine, trigeminal neuralgia, Cluster headache, fibromyalgia syndrome, joint pain, inflammatory pain, arthritis pain, osteoarthritis pain, rheumatoid arthritis pain, tumor pain, cancer pain, visceral pain, somatic pain, musculoskeletal pain, bone Pain, lumbosacral pain, neck pain or upper back pain, diabetic pain, pain caused by spinal cord injury, surgical pain, postoperative pain, acute pain, or with infection, sickle cell anemia, autoimmune disease, multiple sclerosis or Inflammation-related pain, pain caused by injury or surgery, or a combination thereof.
  • the condition that is reduced in therapeutic efficacy due to opioid tolerance is selected from the group consisting of pain associated with diabetic neuropathy, peripheral neuralgia, post-herpetic neuralgia, waist or neck Nerve root pain, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, burning pain, thalamic syndrome, nerve root avulsion, phantom limb pain, pain after thoracotomy, cancer, chemical damage, toxins, nutrition Lack, viral or bacterial infection, temporomandibular joint disorder syndrome, fibromyalgia syndrome, osteoporosis, bone metastasis or other unknown causes of bone pain, gout, fibrinitis, myofascial pain, thoracic outlet syndrome , back or back pain, pelvic pain, heart chest pain, non-cardiac chest pain, spinal cord injury-related pain, central stroke pain, cancer pain, AIDS pain, anti-tumor drug-induced neuropathic pain, sickle
  • the D-amino acid oxidase inhibitor is selected from one or more of the following: CBIO (5-chlorobenzo [d] isoxazol-3-ol, Ferraris et al" J Med Chem 51 : 3357-3359, 2008; Hashimoto et al., Biol Psychiatry 65: 1103-1106, 2009; Horio et al., Open Clin Chem J 2: 16-21, 2009; Gong et al., J Pharmacol Exp Ther 336: 282-293, 2011), AS057278 (5-methylpyrazole-3-carboxylic acid, Adage et al" Eur Neuropsychopharmacol 18: 200-214, 2008; Gong et al., J Pharmacol Exp Ther 336: 282-293, 2011), Compound 8 (4H-thieno [3,2-b]pyrrole-5-carboxylic acid, Sparey et al" Bioorg Med Chem Lett 18: 3386-33
  • the image exhibits tolerance to one or more opioids selected from the group consisting of: alfentanil, fenprozine, afarodidine, anilidine, benzyl Morphine, benzonitrile, buprenorphine, butorphanol, chloredazin, codeine, deoxymorphine, dexamethasone, dextrozine, dienamide, diamorphone, dihydrocodeine , dihydromorphine, dimethacamine, methadol, butylamine, morphine, pellucidum, etazocine, isoxazin, ethmidine, ethylmorphine, ethoxynidazole , etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxyperidine, isomeacone, ketomines, levorphane, levofene, Rofentanil
  • the method when the method is for preventing and/or treating a condition in which the therapeutic efficacy is reduced by opioid tolerance, the method further comprises administering an additional therapeutic agent to the subject.
  • an additional therapeutic agent for example, when used to prevent and/or treat pain, a pain treatment agent can also be administered to the subject, including but not limited to an analgesic such as an opioid analgesic, or a combination thereof.
  • the additional therapeutic agent is selected from the group consisting of opioids, for example selected from one or more of the following opioids: afentanil, allylidine, alfaclodine, Anilididine, benzylmorphine, benzonitrile, buprenorphine, butorphanol, chlordazin, codeine, deoxymorphine, dexamethasin, dextrozine, dipropenamine, diamorphone, Dihydrocodeine, dihydromorphine, dimethacin, methadol, butylamine, morphine, pellucidum, etatazocin, issoxazine, methotrexate, ethylmorphine , ethoxynidazole, etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, oxypeptidine, isomezin, ketomines, levorphan , levophan , levophan
  • the opioid may be morphine or a derivative thereof.
  • the opioid agonist can be a morphine drug such as morphine, hydromorphone, fentanyl, buprenorphine, and buprenorphine.
  • the D-amino acid oxidase inhibitor is administered prior to, concurrently with, or after administration of the opioid.
  • the D-amino acid oxidase inhibitor is administered orally or parenterally, for example, including subcutaneous injection, spinal administration, intracerebral administration, intramuscular injection, nasal administration, intravenous Internal administration and/or intraperitoneal administration.
  • the present disclosure provides a method of preventing and/or treating pain comprising administering an opioid and a D-amino acid oxidase inhibitor to a subject in need thereof.
  • opioids and acid oxidase inhibitors can be used separately and/or separately.
  • the D-amino acid oxidase inhibitor can be administered prior to, concurrently with, and/or after administration of the opioid.
  • the opioid is selected from one or more of the following: alfentanil, allylidine, afarodidine, anilidine, benzylmorphine, benzonitrile, Buprenorphine, butorphanol, chlordazin, codeine, deoxymorphine, dexamethasin, dextrozine, dipropenamine, diamorphone, dihydrocodeine, dihydromorphine, dimethacin , methadol, butylamine, morphine, pellucidum, etazocine, isoglucan, methotrexate, ethylmorphine, ethoxynidazole, etorphine, dihydrogen Trophine, fentanyl and derivatives, hydrocodone, hydromorphone, oxypipetiline, isomeacone, cretophanone, levorphane, levonformane, remifentanil, patidine Pyridinium, m
  • the D-amino acid oxidase inhibitor is selected from one or more of the group consisting of CBIO, Compound 8, Compound 2, AS057278, sodium benzoate and derivatives thereof.
  • the pain is acute pain and/or chronic pain, especially chronic pain, such as cancer pain.
  • the pain may be selected from the following one or Multiple: chronic pain, neuropathic pain, chronic low back pain, headache, migraine, trigeminal neuralgia, cluster headache, fibromyalgia syndrome, joint pain, inflammatory pain, arthritis pain, osteoarthritis pain, Rheumatoid arthritis pain, tumor pain, cancer pain, visceral pain, somatic pain, musculoskeletal pain, bone pain, lumbosacral pain, neck pain or upper back pain, diabetic pain, pain caused by spinal cord injury, surgical pain, Postoperative pain, acute pain, or pain associated with infection, sickle cell anemia, autoimmune disease, multiple sclerosis or inflammation, pain caused by injury or surgery, diabetic neuropathic pain, peripheral neuralgia, postherpetic neuralgia , lumbar or cervical nerve root pain, fibromyalgia, glossopharyngeal neuralgia,
  • the present disclosure provides a method of treating chronic pain, particularly cancer pain, comprising administering to a subject in need thereof an effective amount of a D-amino acid oxidase inhibitor.
  • the D-amino acid oxidase inhibitor is selected from one or more of the following: CBIO, Compound 8, Compound 2, AS057278, sodium benzoate and derivatives thereof.
  • a method of identifying a compound capable of preventing and/or reversing opioid tolerance comprising the steps of: providing a test compound to contact the test compound with an acid oxidase And determining the activity of the acid oxidase; if the test compound is capable of inhibiting the activity of D-amino acid oxidase, the test compound can be used as a compound for preventing and/or reversing opioid tolerance.
  • a compound identified according to the above method can be used for the prevention and/or treatment of a disease whose therapeutic efficacy is lowered due to opioid tolerance.
  • the condition is pain, especially chronic pain.
  • the invention provides a method of identifying a compound capable of preventing and/or reversing opioid tolerance, comprising the steps of: providing a test compound and an opioid prior to administration of the opioid, Simultaneously and/or subsequent administration of the test compound to a test subject, compared to opioid activity prior to administration of the test compound and/or administration of the test compound, if the opioid is administered after administration of the test compound
  • the test compound can be used as a compound for preventing and/or reversing opioid tolerance.
  • the condition is pain, especially chronic pain.
  • an acid oxidase inhibitor for the preparation of a medicament for preventing and/or reversing opioid tolerance is provided.
  • the technical solutions corresponding to the various embodiments involved in the method of the first aspect described above are included.
  • the invention provides the use of an acid oxidase inhibitor in combination with an opioid for the preparation of a medicament for the prevention and/or treatment of pain.
  • an acid oxidase inhibitor in combination with an opioid for the preparation of a medicament for the prevention and/or treatment of pain.
  • an acid oxidase inhibitor for use in preventing and/or reversing opioid tolerance, or in combination with an opioid for preventing and/or treating pain.
  • the technical solutions corresponding to the various embodiments involved in the methods of the first and second aspects described above are included.
  • an acid oxidase inhibitor for the preparation of a medicament for preventing and/or reversing opioid tolerance, or for use in combination with an opioid for the preparation of prophylaxis and/or Or a drug that treats pain.
  • the technical solutions corresponding to the various embodiments involved in the methods of the first and second aspects described above are included.
  • Figure 1 shows the prevention and reversal of morphine tolerance by a single or continuous subcutaneous injection of the acid oxidase inhibitor CBIO.
  • A is a mouse formalin phase I acute pain response
  • B is a phase II chronic pain response.
  • a represents P ⁇ 0.05
  • b represents P ⁇ 0.05.
  • Figure 2 shows the effect of subcutaneous injection of the D- ⁇ acid oxidase inhibitor CBIO on the dose-effect relationship of morphine tolerance for 7 consecutive days.
  • A is the effect of a single injection of different doses of morphine on formalin pain in mice after subcutaneous injection of normal saline for 7 days;
  • B is a 7-day subcutaneous injection of morphine (10 m g / k g ), a single injection is different The effect of dose of morphine on formalin pain in mice;
  • C was a 7-day subcutaneous injection of CBIO (10 mg/kg) + morphine (10 mg/kg), a single injection of different doses of morphine on mice formalin
  • the effect of pain; D is the dose-effect relationship of mouse formalin phase I acute pain morphine;
  • E is the dose-effect relationship of mouse formalin phase II chronic pain morphine.
  • Figure 3 shows the preventive effect of subcutaneous injection of D-J-acid oxidase inhibitors AS057278 (40 mg/kg) and sodium benzoate (400 mg/kg) on morphine tolerance for 7 consecutive days.
  • A is the acute pain response of mouse Formalin phase I
  • B is the chronic pain response of phase II.
  • a represents P ⁇ 0.05
  • b represents P ⁇ 0.05 compared with the corresponding morphine analgesia group.
  • Figure 4 shows a single intrathecal injection of acid oxidase inhibitors CBIO (30 ⁇ g), AS057278 (100 ⁇ g) and sodium benzoate (300 ⁇ g) and reactive oxygen species (ROS).
  • Figure 5 shows single-dose subcutaneous injection of acid oxidase inhibitors CBIO, AS057278 and sodium benzoate in mouse hot plate iris (A, B, C) and hot plate (D, E, F) pain models Immediately reverse the dose-effect relationship of morphine tolerance.
  • Figure 6 shows the effect of single-dose subcutaneous injection of D-acid oxidase inhibitors CBIO, AS057278 and sodium benzoate on the reversal of morphine tolerance in the mouse appendix (A) and hot plate (B) pain models. Relationship and analysis of correlations with inhibition of D-amino acid oxidase activity in rat spinal cord (C and D).
  • Figure 7 shows the effect of spinal cord injection of D-J ⁇ acid oxidase siRNA/DAO on formalin pain in morphine-tolerant rats for 7 consecutive days (A). Effect of spinal cord injection of D-amino acid oxidase siRNA/DAO on DAO expression in spinal cord of morphine-tolerant rats (B). Acute phase I pain map after injection of formalin in rats (C). The dose-effect relationship of the drug to the phase II pain response was calculated by the area under the curve (D).
  • Figure 8 shows the effect of spinal cord injection of D-J ⁇ acid oxidase Virus siRNA/DAO on formalin pain in morphine-tolerant rats for 7 consecutive days (A). Effect of spinal cord injection acid oxidase Virus siRNA/DAO on DAO expression in spinal cord of morphine-tolerant rats (B). Phase I acute pain map after injection of formalin in rats (C). Calculate the pain response of the drug to phase II by the area under the curve Dose-effect relationship (D).
  • the term "treating" means that the target disease or condition and/or any of its symptoms and/or any of its possible complications and/or sequelae of the subject to be treated are radically treated by medical intervention, Eliminating, alleviating, ameliorating, stopping exacerbation, and/or prevention, or causing the subject to be treated to obtain any positive effects in an immediate and/or potential medical sense.
  • prevention refers to preventing, avoiding and/or delaying the occurrence of medical conditions.
  • preventing opioid tolerance means preventing, avoiding, and/or delaying the onset of opioid tolerance.
  • reversal or “disarmed” when used in a medical condition mean that the medical condition that has occurred does not occur again, and/or reduces its severity.
  • reversing/relaxing opioid tolerance refers to the level at which opioid tolerance that has occurred no longer occurs and/or reduces opioid tolerance.
  • D-amino acid oxidase is an oxidoreductase that oxidizes D-amino acids to the corresponding imino acids to produce ammonia. And hydrogen peroxide.
  • DAO usually contains FAD as a cofactor, which is expressed in a wide variety of species from yeast to humans, but not in bacteria and plants.
  • inhibitor means a substance that acts to reduce, block and/or eliminate it.
  • An acid oxidase inhibitor refers to a substance capable of reducing, blocking and/or eliminating D-amino acid oxidase activity, which is capable of inhibiting D-amino acid oxidase activity to reduce, block and/or eliminate acid Oxidase produces biological effects associated therewith. Inhibition of D-amino acid oxidase activity can be achieved in a variety of ways. In one embodiment, a DAO inhibitor can bind DAO and reduce, block and/or eliminate D-amino acid oxidase.
  • a DAO inhibitor can reduce DAO expression by gene silencing of RNA interference and/or abolish DAO expression, thereby inhibiting DAO activity.
  • the DAO inhibitor can be reduced by antisense RNA mechanism And/or eliminate DAO expression to achieve an effect of inhibiting DAO activity.
  • the DAO inhibitor can achieve inhibition of DAO activity by a gene knockout mechanism.
  • opioid can be used interchangeably with “opioids” and “opioids”, which means that its pharmacological activity is exerted by acting on opioid receptors.
  • opioid receptors One of the most important activities of a class of drugs is narcotic analgesia, which is used to treat a wide range of acute and chronic pain.
  • opioids exert their pharmacological activity by stimulating opioid receptors, they are also known as opioid receptor agonists or opioid agonists.
  • the opioid receptor is mainly in the central nervous system (brain). In the spinal cord), it is also expressed in the peripheral nervous system such as the digestive tract. Based on this, the therapeutic efficacy and adverse reactions of opioid receptors are also mainly manifested in these systems and tissues.
  • the opioid agonists used in the opening include, but are not limited to, alfentanil, fenprodidine, afarodidine, anilidine, benzylmorphine, benzimidate, buprenorphine, buttonol , chlordazin, codeine, deoxymorphine, dexamethasin, dextrozine, dipropenamine, diamorphone, dihydrocodeine, dihydromorphine, dimethacone, methadol, butylamine , morphine, piperazine, etazocine, isoxazin, methotrexate, ethylmorphine, ethoxynidazole, etorphine, dihydroetorphine, fentanyl and derivatives , hydrocodone, hydromorphone, hydroxyperidine, isomeacone, cretophanone, levorphane, leflufendane, remifentanil, phenidine, m
  • Opioid tolerance can be used interchangeably with “opioid tolerance” and “opioid tolerance” as used in the content.
  • “Tolerance” refers to a process of neurological adaptation in which the receptor is less sensitive to ligands and results in a lowering of the drug's action.
  • “Opioid tolerance” refers to a neurological adaptation process in which opioid receptors have reduced agonistic effects on opioid receptors, resulting in a corresponding decrease in their drug activity. Due to the development of opioid tolerance, the efficacy (such as analgesia) is continuously reduced, and the dose of opioids (such as morphine) has to be increased in the course of treatment (such as analgesia). Occasionally, opioid therapy is often unavoidable because of the inability to produce adequate therapeutic effects or the serious side effects due to increased doses.
  • D-amino acid oxidase inhibitors including CBIO, AS057278 and sodium benzoate
  • opioid receptor agonists such as morphine
  • the site of action in the spinal cord, with spinal cord D-amino acid oxidase activity Sexual inhibition is positively correlated.
  • D-amino acid oxidase inhibitors prevent or block opioid tolerance.
  • the present disclosure provides a method of preventing and/or reversing opioid tolerance comprising administering an effective amount of a D-amino acid oxidase inhibitor to a subject in need thereof.
  • the method is for preventing and/or treating a condition which is reduced in therapeutic efficacy due to opioid tolerance, the condition being capable of achieving prevention and/or opioid tolerance by inhibiting D-amino acid oxidase Get prevented and / or treated.
  • the condition can be pain, including but not limited to acute and/or chronic pain, especially chronic pain, such as cancer pain.
  • the condition that is reduced in therapeutic efficacy due to opioid tolerance is selected from the group consisting of chronic pain, cancer pain, neuropathic pain, chronic low back pain, headache, migraine, trigeminal neuralgia, Cluster headache, fibromyalgia syndrome, joint pain, inflammatory pain, arthritis pain, osteoarthritis pain, rheumatoid arthritis pain, tumor pain, cancer pain, visceral pain, somatic pain, musculoskeletal pain, bone Pain, lumbosacral pain, neck pain or upper back pain, diabetic pain, pain caused by spinal cord injury, surgical pain, postoperative pain, acute pain, or with infection, sickle cell anemia, autoimmune disease, multiple sclerosis or Inflammation-related pain, pain caused by injury or surgery, or a combination thereof.
  • the condition that is reduced in therapeutic efficacy due to opioid tolerance is selected from the group consisting of pain associated with diabetic neuropathy, peripheral neuralgia, post-herpetic neuralgia, waist or neck Nerve root pain, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, burning pain, thalamic syndrome, nerve root avulsion, phantom limb pain, pain after thoracotomy, cancer, chemical damage, toxins, nutrition Lack, viral or bacterial infection, temporomandibular joint disorder syndrome, fibromyalgia syndrome, osteoporosis, bone metastasis or other unknown causes of bone pain, gout, fibrinitis, myofascial pain, thoracic outlet syndrome , back or back pain, pelvic pain, heart chest pain, non-cardiac chest pain, spinal cord injury-related pain, central stroke pain, cancer pain, AIDS pain, anti-tumor drug-induced neuropathic pain, sickle
  • the D-amino acid oxidase inhibitor is selected from one or more of the following: CBIO (5-chlorobenzo [d] isoxazol-3-ol> Ferraris et al" J Med Chem 51 : 3357-3359, 2008; Hashimoto et al., Biol Psychiatry 65: 1103-1106, 2009; Horio et al., Open Clin Chem J 2: 16-21, 2009; Gong et al., J Pharmacol Exp Ther 336: 282-293, 2011), AS057278 (5-methylpyrazole-3-carboxylic acid, Adage et al" Eur Neuropsychopharmacol 18: 200-214, 2008; Gong et al., J Pharmacol Exp Ther 336: 282-293, 2011), Compound 8 (4H-thieno [3,2-b]pyrrole-5-carboxylic acid, Sparey et al" Bioorg Med Chem Lett 18: 3386-33
  • the image exhibits tolerance to one or more opioids selected from the group consisting of: afentanil, fenprozine, afarodidine, anili Ding, benzylmorphine, benzonitrile, buprenorphine, butorphanol, chloredazin, codeine, deoxymorphine, dexamethasin, dextrozine, dienamide, diamorphone, dihydrogen Codeine, dihydromorphine, dimethacone, methadol, butylamine, morphine, pelmatone, etazocine, isosamine, metformin, ethylmorphine, B Oxynitrazole, etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypitidine, isomezicin, ketomines, levorphane, left Fentan, remifentanil, phenidine
  • the method when the method is for preventing and/or treating a condition in which the therapeutic efficacy is reduced by opioid tolerance, the method further comprises administering an additional therapeutic agent to the subject.
  • an additional therapeutic agent for example, when used to prevent and/or treat pain, a pain treatment agent can also be administered to the subject, including but not limited to an analgesic such as an opioid analgesic, or a combination thereof.
  • the additional therapeutic agent is selected from the group consisting of opioids, such as one or more opioids selected from the group consisting of: alfentanil, allylidine, alfalogine, Anilididine, benzylmorphine, benzonitrile, buprenorphine, butorphanol, chlordazin, codeine, deoxymorphine, dexamethasin, dextrozine, dipropenamine, diamorphone, Dihydrocodeine, dihydromorphine, dimethacin, methadol, butylamine, morphine, pellucidum, etatazocin, issoxazine, methotrexate, ethylmorphine , ethoxynidazole, etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, oxypeptidine, isomezin, ketomines, levorphan , levophan , levophan
  • the opioid may be morphine or a derivative thereof.
  • the opioid agonist can be a morphine drug such as morphine, hydromorphone, fentanyl, buprenorphine, and buprenorphine.
  • the D-amino acid oxidase inhibitor is administered prior to, concurrently with, or subsequent to the administration of the opioid.
  • the D-amino acid oxidase inhibitor is administered orally or parenterally, for example, including subcutaneous injection, spinal, intracerebral administration, intramuscular injection, nasal administration, intravenous administration. And / or intraperitoneal administration.
  • the disclosure provides a method of preventing and/or treating pain comprising administering to a subject in need thereof an opioid and a D-amino acid oxidase inhibitor.
  • opioids and acid oxidase inhibitors may be administered separately and/or together.
  • the D-amino acid oxidase inhibitor can be administered prior to, concurrently with, and/or after administration of the opioid.
  • the opioid is selected from one or more of the following: alfentanil, allylidine, afarodidine, anilidine, benzylmorphine, benzonitrile, Buprenorphine, butorphanol, chlordazin, codeine, deoxymorphine, dexamethasin, dextrozine, dipropenamine, diamorphone, dihydrocodeine, dihydromorphine, dimethacin , methadol, butylamine, morphine, piperazine, etazocine, isoxazin, metformin, ethylmorphine, ethoxynidazole, etorphine, dihydrogen Trophine, fentanyl and derivatives, hydrocodone, hydromorphone, oxypiperidine, isomeacone, cretophanone, levorphane, levonofan, rofentanil, tifenidine , meptazin, metazo
  • the D-amino acid oxidase inhibitor is selected from one or more of the following: CBIO, Compound 8, Compound 2, AS057278, sodium benzoate and its derivatives Creature.
  • the pain is acute pain and/or chronic pain, especially chronic pain, such as cancer pain.
  • the pain may be selected from one or more of the following: chronic pain, neuropathic pain, chronic low back pain, headache, migraine, trigeminal neuralgia, cluster headache, fibromyalgia syndrome, joint Pain, inflammatory pain, arthritis pain, osteoarthritis pain, rheumatoid arthritis pain, tumor pain, cancer pain, visceral pain, somatic pain, musculoskeletal pain, bone pain, lumbosacral pain, neck pain or upper back Pain, diabetic pain, pain caused by spinal cord injury, surgical pain, postoperative pain, acute pain, or pain associated with infection, sickle cell anemia, autoimmune disease, multiple sclerosis or inflammation, caused by injury or surgery Pain, diabetic neuropathic pain, peripheral neuralgia, postherpetic neuralgia, lumbar or cervical radiculopathy, fibromyalgia, glossopharyngeal neuralgi
  • the disclosure provides a method of treating chronic pain, particularly cancer pain, comprising administering to a subject in need thereof an effective amount of a D-amino acid oxidase inhibitor.
  • the D-amino acid oxidase inhibitor is selected from one or more of the group consisting of CBIO, Compound 8, Compound 2, AS057278, sodium benzoate and derivatives thereof.
  • a method of identifying a compound capable of preventing and/or reversing opioid tolerance comprising the steps of: providing a test compound to contact the test compound with an acid oxidase And determining the activity of the acid oxidase; if the test compound is capable of inhibiting the activity of D-amino acid oxidase, the test compound can be used as a compound for preventing and/or reversing opioid tolerance.
  • a compound identified according to the above method can be used for the prevention and/or treatment of a disease whose therapeutic efficacy is lowered due to opioid tolerance.
  • the condition is pain, especially chronic pain.
  • the invention provides another method of identifying a compound capable of preventing and/or reversing opioid tolerance, comprising the steps of: providing a test compound and an opioid prior to administration of the opioid, Applying the test compound to the test subject simultaneously and/or afterwards, Comparing the activity of the opioid before administration of the test compound and/or prior to administration of the test compound, if the level of opioid activity is increased after administration of the test compound, the test compound can be used as a prophylactic / or reverse opioid-tolerant compounds.
  • a compound identified according to the above methods can be used to prevent and/or treat a condition that reduces its therapeutic efficacy due to opioid tolerance.
  • the condition is pain, especially chronic pain.
  • mice Male Swiss mice (20 ⁇ 25 g , Shanghai Slack Laboratory Animals Co., Ltd.), free drinking water, eating, divided into 10 groups, 4 in each group. Three groups of mice were injected subcutaneously with normal saline (10 ml/kg) twice daily for 7 days. On the 8th day, physiological saline (10 ml/kg) and CBIO (10 mg/kg, from Maybridge Chemicals, respectively) were administered.
  • mice were injected subcutaneously with CBIO (10 mg/kg) or morphine (10 mg/kg), CBIO (10 mg/kg) or morphine (5 mg/kg) were given twice daily for 7 days and 8 days.
  • Group 2 mice were injected subcutaneously with CBIO (10 mg/kg) or morphine (10 mg/kg).
  • mice twice daily for 7 days, on the 8th day, morphine (5 mg/kg) or CBIO (10 mg/kg); 2 groups of mice were injected subcutaneously with CBIO (10 mg/kg) or CBIO (10 mg) /kg ) + morphine (10 mg/kg), twice daily for 7 days, on the 8th day, saline (10 ml/k g ) or morphine (5 mg/kg); group 1 mice subcutaneously injected with morphine (10 mg/kg), twice daily for 7 days (14 times in total), the 14th dose was given CBIO (10 mg/kg), and the 8th day was given morphine (5 mg/kg)êt Day 8 After 20 minutes of administration, the mice Injection of 10 ⁇ 5% formalin on the right hind paw Pain was observed.
  • mice Male Swiss mice (20 ⁇ 25 g , Shanghai Slack Laboratory Animals Co., Ltd.), free drinking water, eating, divided into 18 groups, 4 in each group. Six groups of mice were injected subcutaneously with normal saline (10 ml/kg) twice daily for 7 days. On the 8th day, saline (10 ml/kg) or morphine (0.1, 0.3, 1, 3 ⁇ 10 mg) were administered.
  • mice were injected subcutaneously with morphine (10 m g / k g ) twice daily for 7 consecutive times
  • physiological saline 7j (10 ml/kg) or morphine (0.3, 1, 3, 10 and 30 mg/kg) were given respectively
  • 6 groups of mice were injected subcutaneously with CBIO (10 mg/kg) + morphine ( 10 mg/kg), twice daily for 7 days, on the 8th day, saline (10 ml/kg) or morphine (0.1, 0.3, 1, 3 and 10 mg/kg) were administered.
  • mice After 20 minutes of dosing on day 8, mice were injected with 10 ⁇ l of 5% formalin in the right hind paw, and pain was observed 0-5 minutes after the formalin injection (phase I acute reaction) and 20-40 minutes. (Chronic phase II chronic reaction) Mice continued to have lameness time as an indicator of pain. The results of the experiment are shown in Fig. 2. In the control mice in which the saline was continuously injected subcutaneously on the 7th day, a single dose of morphine (0, 0.1, 0.3, 1, 3 and 10 mg/kg) inhibited the dose in a dose-dependent manner. Malin I phase acute pain and phase II chronic pain (Fig.
  • mice Male Swiss mice (20 ⁇ 25 g , Shanghai Slack Laboratory Animals Co., Ltd.), free drinking water, eating, divided into 5 groups, 4 in each group. Two groups of mice were injected with normal saline (10 ml/kg) twice a day for 7 days, and on the 8th day, saline (10 ml/kg) or morphine (5 mg/kg) were given respectively.
  • mice Subcutaneous injection of morphine (10 mg/kg), AS057278 (40 mg/kg, from Sigma-Aldrich, St Louis, MO) + morphine (10 mg/kg) or sodium benzoate (400 mg/kg, from Sinopharm Group) , Shanghai, China) + (10 mg/kg), twice daily for 7 days, on the 8th day, morphine (5 mg/kg).
  • mice were injected with 10 ⁇ l 5% formalin for pain in the right hind paw, and 0-5 minutes (phase I acute reaction) and 20-40 minutes after formalin injection. (phase II chronic reaction) mice continue to lick Full time as an indicator of pain.
  • AS057278 and tyrosine can prevent morphine tolerance after 7 days, and the inhibition rates of formalin phase I acute pain and phase II chronic pain by single dose morphine are 76.1% and 100%, respectively;
  • Sodium benzoate combined with morphine for 7 days also prevented the tolerance of morphine production.
  • the inhibition rates of formalin phase I acute pain and phase II chronic pain were 69.8% and 89.1%, respectively.
  • the results showed that AS057278 combined with sodium benzoate and morphine can effectively prevent the tolerance of analgesia.
  • Rats received intrathecal morphine (50 ⁇ g/10 ⁇ l/rat) for 5 days and developed significant tolerance.
  • Single-dose administration of CBIO (30 g), AS057278 (100 g), sodium benzoate (300 ⁇ g) and PBN (1 mg) in the spinal cord can almost completely reverse the tolerance that morphine has produced, ie, a single dose of morphine.
  • the acute pain inhibition rates of these rats in formalin phase I were 70.8%, 69.3%, 79.5% and 54.3%, respectively.
  • mice Male Swiss mice (20 ⁇ 25 g , Shanghai Slack Laboratory Animals Co., Ltd.), free drinking water, eating, divided into 15 groups, 4 in each group. Two groups of mice were injected subcutaneously with normal saline (10 ml/kg) twice a day for 7 consecutive days. The appendix and hot plate pain thresholds were measured before the 8th day of administration, and then saline (10 ml/k g was administered ). 13 groups of mice were injected subcutaneously with morphine (10 m g / k g ) twice daily for 7 consecutive days.
  • the appendix and hot plate pain thresholds were measured before dosing on day 8 and then given 1, 3 and 10 mg/kg CBIO, 3, 10 and 100 mg/kg AS057278 and 10, 30, 100 and 300 m g / k g sodium benzoate. After 15 minutes of administration of saline or D-amino acid oxidase inhibitor, all mice were examined for appendix and hot plate pain thresholds, followed by morphine (5 mg/kg), and mice were tested at 0.5, 1 and 2 hours, respectively. Tail and hot plate pain threshold. The effects of different doses of each drug on the appendix and hot plate pain in mice were compared, and the threshold net value and the area under the curve (AUC) within 2 hours were calculated. The results of the experiment are shown in Figure 5.
  • the subcutaneous injection of morphine for 7 consecutive days produced significant tolerance.
  • the single-dose injection did not cause analgesia on mouse tail and hot plate pain;
  • single dose subcutaneous injection of CBIO, AS057278 and sodium benzoate It can reverse morphine tolerance in a dose-dependent manner.
  • the dose-response analysis showed that the maximum blocking rate of CBIO, AS057278 and sodium benzoate blocking morphine tolerance was 100%, and the ED50 was 1.0, 2.5 and 40.5 mg/kg in the mouse appendicitis model, respectively.
  • the mouse hot plate pain model was 1.1, 7.4, and 50.4 mg/kg, respectively (Fig. 6A and Fig. 6B).
  • the rats in the saline (10 ml/kg) + PEI (7.5) group were injected subcutaneously with 10 ml/kg saline, and normal saline (10 ml/kg).
  • + PEI (7.5 ⁇ ⁇ ) morphine (10 mg/kg) + PEI (7.5), morphine (10 mg/kg) + PEI (7.5) + Nonsense siRNA (5) and morphine (10 mg/kg) + PEl ( 7.5) + siRNA/GLP-lr
  • the siRNA/DAO sequence is 5'-GGAGUGAAGUUCAUCCAUCUU-375'-GAUGGAUGAACUUCACU CCUU-3'
  • the Non-sense siRNA sequence is 5,-UUC UCC GAA CGU GUC ACG UUU-375'-ACG UGA CAC GUU CGG AGA AUU-3O Experimental Results As shown in Fig.
  • DAO gene expression was prepared by adding 1 ml of TRIzol solution (Invitrogen, Grand Island, NY, USA) to 100 mg tissue.
  • the DAO primer sequence is: 5'-CCCTTTCTGGAAAAGCACAG-375'-CTCCTCTCACCACCTCTTC G-3', the GAPDH primer sequence is:
  • the rats in the physiological salt 10 ml/kg 20 minutes before the experiment were injected subcutaneously with 10 ml/kg normal saline, normal saline (10 ml/kg), and morphine (10 mg/ Kg Virus-nonsense siRNA and morphine (10 mg/kg) +Virus-siRNA/DAO rats were injected subcutaneously with 10 mg/kg morphine, and the rats were observed with formalin-induced pain model to analyze the analgesic relationship.
  • the shRNA/DAO sequence of adenovirus was 5,-GATCCGGAGTGAAGTTCATCCATCTTCAAGAGAGAGGGATGA ACTTCACTCCTTTTTTA-3', and the shRNA/Non-sense siRNA sequence was 5'-GATCCGCCAGCTGATACTAACTCCTTCAAGAGAGGAGTTAGTA TCAGCTGGCTTTTTTA-3.
  • the results are shown in Figure 8. After 7 days of intravenous saline injection, Subcutaneous morphine (10 mg/kg) was effective in inhibiting formalin acute pain (phase I response, Figure 8C) and chronic pain (phase II response, Figure 8D) compared with the 8th day of subcutaneous injection of saline. The inhibition rates were 90.4 and 98.9%, respectively.
  • Rats were injected with morphine (10 mg/kg) + Virus-Nonsense siRNA for 7 consecutive days. After 8 days of subcutaneous injection of morphine (10 mg/kg), the rats developed obvious analgesia. Make Tolerance, acute pain in rats formalin (I-phase reaction) and chronic pain (II Reaction) Inhibition rate decreased to 20.5% and 5.2%, respectively, for 7 consecutive Daily injection of morphine (10 mg/kg) +Virus-siRNA/DAO completely blocked the analgesic effect of subcutaneous morphine (10 m g /k g ) on day 8 and acute to formalin I in rats The analgesic inhibition rates of pain and phase II chronic pain were 69.2% and 84.9%, respectively.
  • DAO gene expression was prepared by adding 1 ml of TRIzol solution (Invitrogen, Grand Island, NY, USA) to 100 mg tissue. 1000 rpm, 15 s), extract total tissue mRNA according to the instructions, and reverse-transcribe into total cDNA according to 1 total RNA sample using ReverTra Ace qPCR RT-Kit (Toyobo Co., Ltd., Osaka, Japan), in Mastercycler® ep Realplex (Eppendorf AG, Hamburg, Germany) machine, real-time quantitative PCR experiments were performed using the Realmaster Mix (SYBR Green I) (Tiangen Biotech Co., Ltd., Beijing, China) method.
  • the DAO primer sequence is: 5'-CCCTTTCTGGAAAAGCACAG-375'-CTCCTCTCACCACCTCTTC G-3'
  • the GAPDH primer sequence is:

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Abstract

L'invention porte sur un inhibiteur de D-acide aminé oxydase pour la prévention et/ou l'inversion de la tolérance aux osopioïdes et sur un procédé utilisant l'inhibiteur de D-acide aminé pour la prévention et/ou l'inversion de la tolérance aux osopioïdes. L'invention porte également sur un procédé d'utilisation de l'inhibiteur de la D-acide aminé oxydase pour la prévention et/ou le traitement de la douleur et sur un procédé pour l'identification d'un composé pour la prévention et/ou l'inversion de la tolérance aux osopioïdes.
PCT/CN2012/074062 2011-04-14 2012-04-16 Inhibiteur de d-acide aminé oxydase pour la prévention et/ou l'inversion de la tolérance aux osopioïdes WO2012139529A1 (fr)

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CN101511832A (zh) * 2006-06-30 2009-08-19 塞普拉科有限公司 D-氨基酸氧化酶的稠合杂环抑制剂

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101511832A (zh) * 2006-06-30 2009-08-19 塞普拉科有限公司 D-氨基酸氧化酶的稠合杂环抑制剂

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MASANOBU YOSHIKAWA ET AL.: "Acute treatment with morphine augments the expression of serine racemase and D-amino acid oxidase mRNAs in rat brain", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 525, 2005, pages 94 - 97 *
vol. 25, 2009 *
WENJUAN ZHAO ET AL.: "Inhibition of D-Amino-Acid Oxidase Activity Induces Pain Relief in Mice", CELL MOL NEUROBIO, vol. 28, no. 4, 2008, pages 581 - 590 *

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