WO2002042765A1 - Remedes destines a des troubles fonctionnels digestifs et procede de selection - Google Patents

Remedes destines a des troubles fonctionnels digestifs et procede de selection Download PDF

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Publication number
WO2002042765A1
WO2002042765A1 PCT/JP2001/010152 JP0110152W WO0242765A1 WO 2002042765 A1 WO2002042765 A1 WO 2002042765A1 JP 0110152 W JP0110152 W JP 0110152W WO 0242765 A1 WO0242765 A1 WO 0242765A1
Authority
WO
WIPO (PCT)
Prior art keywords
receptor subtype
binding affinity
adrenergic receptor
selective
dorenari
Prior art date
Application number
PCT/JP2001/010152
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English (en)
Japanese (ja)
Inventor
Osamu Yamamoto
Original Assignee
Nippon Shinyaku Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nippon Shinyaku Co., Ltd. filed Critical Nippon Shinyaku Co., Ltd.
Priority to AU2002224058A priority Critical patent/AU2002224058A1/en
Publication of WO2002042765A1 publication Critical patent/WO2002042765A1/fr

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Classifications

    • 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
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Gastrointestinal dysfunction therapeutic agent and screening method Gastrointestinal dysfunction therapeutic agent and screening method
  • the present invention relates to (3 ⁇ 42B adrenaline receptor subtype-selective antagonism, 2C adrenaline receptor subtype-selective antagonism or 2B / 2C (“2 ⁇ and 2C”. The same applies hereinafter.)
  • the present invention relates to a method for screening a medicament for regulating gastrointestinal motility, which uses selective antagonism of adrenergic receptor subtype as an index.
  • the present invention provides a method for selectively treating a 2 ⁇ -adrenergic receptor subtype selective antagonist, a 2C-adrenergic receptor subtype-selective antagonist, or an OC 2B / 2C adrenaline receptor subtype-selective antagonist.
  • the present invention relates to a pharmaceutical composition for regulating gastrointestinal motility, which is contained as a component.
  • the pharmaceutical composition of the present invention has a gastrointestinal motility regulating effect, and is useful for treating irritable bowel syndrome.
  • IBS Irritable bowel syndrome
  • the number of potential patients is also said to be 20% of the population, and it is expected that the number of IBS patients will increase due to the increase in stress in the social environment and the increase in patient awareness of IBS (Internal Medicine 77: 293) -299, 1996, Medical Practice 17: 591-594, 2000
  • IBS Intra-astolic hypertension
  • laxatives include adiarrheals, adiarrheals, adiarrheals, adiarrheals, adiarrheals, adiarrheals, adiarrheals, adiarrheals, adiarrheals, adiarrheals, adiarrheals, intestinal drugs, gastrointestinal motility regulators, and other antidepressants and anxiolytics depending on psychiatric symptoms.
  • the alpha 2 A Dorenarin receptors are known the existence of three subtypes. Initially, human platelets were used to identify the human 2-adrenergic receptor subtype, followed by Southern analysis of the human genome and cDNA libraries. Both the 2B adrenergic receptor subtype and the 2C adrenergic receptor subtype were identified. 0! 2A Oyobihi 2C A Dorenari emissions receptor subtypes are widely distributed in the brain and end treetops tissue, (3 ⁇ 4 2B A Dorenarin receptor subtype is widely distributed in peripheral tissues.
  • Non 2A ⁇ Dorenari emissions receptor subtypes It has been reported that the agonist effect via antagonism is analgesia, sedation, suppression of spontaneous movement, hypothermia, blood pressure decrease, bradycardia, suppression of small intestinal motility, and suppression of gastrointestinal secretion (J. Pharmacol. Exp. Ther. 270: 958-972, 1994; Br. J. Pharmacol. 122: 1339-1344, 1997; Mol. Pharmacol. 56: 154-161, 1999; J. Pharmacol. Exp. Ther. 290: 403-412, 1999, Science 273: 801-803, 1996, Br. J. Pharmacol. 117: 787-792, 1996, Naunyn-Schmiedeberg's Arch. Pharmacol. 356: 248-256, 1997, Br. J. Pharmacol. 120: 892- 898, 1997) On the other hand, the physiological role of the £ 3 ⁇ 42B / 2C adrenaline receptor subtype is poorly understood.
  • any of the subtypes is gastrointestinal motility. It is not known whether it is involved in maintaining homeostasis, ie, regulating gastrointestinal motility.
  • An object of the present invention is to provide a pharmaceutical composition for treating irritable bowel syndrome, which has an excellent gastrointestinal motility regulating action and is highly safe, and a method for screening the same.
  • the present inventors have found that a selective 2B-adrenergic receptor antagonist, a selective K2C-adrenergic receptor antagonist or a2B / 2C-adrenergic receptor selective antagonist achieves the above object. Thus, the present invention has been completed.
  • the present invention provides a selective 2B-adrenergic receptor antagonist, ⁇ 3 ⁇ 42C-adrenergic A pharmaceutical composition for regulating gastrointestinal motility, comprising a phosphorus receptor selective antagonist or a 2B / 2C adrenergic receptor selective antagonist as an active ingredient.
  • the present invention is based on the selective antagonism of human 2B adrenergic receptor, the selective antagonism of 0! 2C adrenaline receptor or the selective antagonism of human 2B / 2C adrenaline receptor. This is a method for screening a drug for regulating tube movement.
  • alpha 2.alpha A Dorenarin receptor antagonism is not involved in gastrointestinal motility regulation
  • alpha 2.beta A Dorenari emissions receptor antagonism is not involved in gastrointestinal motility regulation
  • alpha 2.beta A Dorenari emissions receptor antagonism is involved in gastrointestinal motility regulation
  • a 2C A Dorenari emissions receptor ⁇ anti action or a 2B / 2C ⁇ Drainergic receptor antagonism is involved in gastrointestinal motility regulation.
  • the drug for the treatment of genital bowel syndrome can be screened.
  • Examples of the active ingredient of the pharmaceutical composition of the present invention include a 2-adrenergic receptor selective antagonist, (3 ⁇ 42C adrenergic receptor selective antagonist or a 2B / 2C adrenaline receptor selective antagonist) Any compound having any chemical structure can be used in the present invention.
  • the selective antagonism of human 2B-adrenergic receptor means that it preferentially binds to human 213a-adrenergic receptor over CK2A and human 2C- adrenergic receptor, Means an action that inhibits the effect of the acting drug.
  • the binding affinity for ⁇ 2 ⁇ adrenergic receptor is preferably at least 5 times, more preferably at least 10 times, and more preferably at least 20 times higher than the 2 ⁇ and a 2C adrenergic receptor binding affinities. Is more preferable.
  • the shed 2 ⁇ A Dorenarin receptor selective antagonist is meant a compound that shows a 2 ⁇ A Dorenarin receptor selective antagonism shed.
  • the selective antagonism of 2C- adrenergic receptor is defined as the ⁇ 2 ⁇ and ⁇ 2 ⁇ binding to the 2C- adrenergic receptor preferentially over the 2 ⁇ -adrenergic receptor and the effect of an agonist on the 2C- adrenergic receptor. Means an inhibitory action.
  • the binding affinity for the 2C and adrenergic receptor is 2A and the adrenergic receptor binding affinity. It is preferably at least 5 times, more preferably at least 10 times, even more preferably at least 20 times, than the property.
  • a 2C-adrenergic receptor-selective antagonist means a compound that exhibits a Qi 2C-adrenergic receptor-selective antagonistic action.
  • Dorenari emissions receptor binds preferentially Nihi 2 ⁇ Oyobihi 2C A Dorenarin receptor, shed 2
  • the binding affinity for ⁇ 2 and 2C adrenergic receptors is preferably 5 times or more, more preferably 10 times or more, and more preferably 20 times or more than that of CK 2A adrenaline receptor. Is more preferable.
  • the 2B / 2C adrenergic receptor selective antagonist refers to a compound exhibiting a 2B / 2C adrenergic receptor selective antagonism.
  • Examples of the ⁇ 2-adrenergic receptor selective antagonist, the 2C-adrenergic receptor selective antagonist or the 3 ⁇ 42B / 2C-adrenergic receptor selective antagonist according to the present invention include ARC239 (2- ⁇ 2- [4- (2-methoxyphenyl) -l-piperazinyl] ethyl ⁇ -4, 4- dimethyl-1, 3 (2H, 4H) -isoqu inol inedione ⁇ J. Pharmacol. Exp. Ther. 270: 958- 972, 1994), or
  • aThe binding affinity for 2A, ⁇ 2 ⁇ and CK 2C adrenergic receptors can be measured according to a known method, for example, the method described in f J. Pharmacol. Exp. Ther. 271: 1558-1565, 1994. it can.
  • Antagonism to each receptor can be confirmed by a known method, for example, the method described in Eur. J. Pharmacol. 335: 53-63, 1997 or Eur, J. Pharmacol. 361: 1-15, 1998.
  • the ⁇ selective antagonist for 2-adrenergic receptor, CK 2C-adrenergic receptor-selective antagonist or (3 ⁇ 42B / 2C-adrenergic receptor-selective antagonist includes gastrointestinal motility regulation or IBS Low toxicity compared to therapeutic dose Devour.
  • the compound can be used as a medicament as it is as the free acid, or can be used in the form of a pharmaceutically acceptable salt by a known method.
  • a pharmaceutically acceptable salt examples include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as potassium salt.
  • the compound having the following formula can be used as a medicament as it is as a free base, but can also be used in the form of a pharmaceutically acceptable salt by a known method.
  • salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, acetic acid, cunic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, and p-toluenesulfonate.
  • salts of organic acids such as benzenesulfonic acid and methanesulfonic acid.
  • the CK 2B adrenerin receptor selective antagonist, the 2C adrenerin receptor selective antagonist or the C3 ⁇ 42B / 2C adrenerin receptor selective antagonist according to the present invention are shown in the test examples described below. As described above, it has an excellent gastrointestinal motility regulating effect and has only minor central side effects, so that it can be used for gastrointestinal motility regulation and treatment of IBS.
  • the CK 2B adrenergic receptor selective antagonist, the 2C adrenergic receptor selective antagonist or the Q! 2B / 2C adrenergic receptor selective antagonist according to the present invention is administered as a medicament.
  • the ⁇ 2 ⁇ - adrenergic receptor-selective antagonist, the 2C-adrenergic receptor-selective antagonist or the ⁇ 3 ⁇ 42B / 2C-adrenergic receptor-selective antagonist according to the present invention may be used directly or as a pharmaceutical.
  • / ⁇ is administered to animals, including humans, as a pharmaceutical composition containing it.
  • the pharmaceutical composition may be administered in dosage unit form. Is desirable.
  • the pharmaceutical composition according to the present invention can be administered orally, intravenously, intracellularly, topically (such as transdermally) or rectally. Needless to say, it is administered in a dosage form suitable for these administration methods. Oral administration and intravenous administration are particularly preferred.
  • the dose of the pharmaceutical composition for regulating gastrointestinal motility or the pharmaceutical composition for treating IBS is preferably determined in consideration of the patient's condition such as age and weight, the administration route, the nature and extent of the disease, etc. .
  • the effective component amount of the compound of the present invention for adults is generally in the range of 0.001 to 1000 mg / human, preferably in the range of 0.1 to 100 mg / human. is there.
  • lower doses may be sufficient, and conversely, higher doses may be required. It can also be administered in 2 to 4 divided doses per day.
  • solid or liquid dosage units such as powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, and other dosage forms It can be done by
  • Powders are prepared by comminuting the active substance to an appropriate degree. Powders are prepared by comminuting the active substance to a suitable fineness and then mixing with a similarly comminuted pharmaceutical carrier such as starch, edible carbohydrates such as mannitol, and the like. If necessary, flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added.
  • a similarly comminuted pharmaceutical carrier such as starch, edible carbohydrates such as mannitol, and the like.
  • flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added.
  • Capsules are manufactured by filling powdered powders, powders, or granules as described above into granules as described in the section on capsules, for example, into capsules such as gelatin capsules. Is done. Lubricants and superplasticizers, such as cod syrup, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol are mixed into a powdered form, The filling operation can be performed later.
  • Disintegrators and solubilizers for example, canolepoximetinolese / rerose, canoleboximethy / resenorelose force / resin, low-substituted hydroxypropinolese / rerose, closkanoleme rozen sodium, carboxymethyl starch sodium, carbonate
  • canolepoximetinolese / rerose canoleboximethy / resenorelose force / resin
  • low-substituted hydroxypropinolese / rerose low-substituted hydroxypropinolese / rerose
  • closkanoleme rozen sodium carboxymethyl starch sodium
  • carbonate closkanoleme rozen sodium
  • the fine powder of this product can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant, and wrapped in a gelatin sheet to form a soft capsule.
  • Tablets are made by adding an excipient, forming a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and compressing.
  • the powder mixture is prepared by mixing the appropriately powdered material with the above-mentioned diluents and bases and, if necessary, binding agents (e.g., sodium carboxymethylcellulose, methinoresenololose, hydroxypropinolemethinoresenorelose, Gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc.), dissolution retarders (eg, paraffin), resorbents (eg, quaternary salts) and adsorbents (eg, bentonite, kaolin, diphosphate) ) May also be used in combination.
  • binding agents e.g., sodium carboxymethylcellulose, methinoresenololose, hydroxypropinolemethinoresenorelose, Gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc.
  • dissolution retarders eg, paraffin
  • resorbents eg, quaternary salts
  • adsorbents e
  • the powder mixture can first be moistened with a binder, for example syrup, starch paste, gum arabic, cellulose solution or polymer solution, stirred and mixed, dried and pulverized into granules.
  • a binder for example syrup, starch paste, gum arabic, cellulose solution or polymer solution
  • stirred and mixed dried and pulverized into granules.
  • the granules thus produced can be prevented from adhering to each other by adding stearic acid, stearic acid salt, talc, mineral oil or the like as a lubricant.
  • the lubricated mixture is then tableted.
  • the uncoated tablets thus produced can be coated with a film-coated sugar coating.
  • the drug may be directly tabletted after being mixed with a fluid inert carrier without going through the steps of granulation and slag formation as described above.
  • Transparent or translucent protective coatings consisting of a sealed shellac coating, coatings of sugar or polymeric materials, and polish coatings of blacks can also be used.
  • Capsules are prepared by dissolving the compound in an appropriate flavoring solution, and elixirs are prepared through the use of a non-toxic alcoholic carrier.
  • the suspension is It is formulated by dispersing the compound in a non-toxic carrier.
  • Solubilizers and emulsifiers eg, ethoxylated isostearyl alcohols, polyoxetylene sorbitol esters
  • preservatives eg, palmit oil, saccharin
  • flavoring agents eg, palmit oil, saccharin
  • dosage unit formulations for oral administration may be encapsulated in a mic mouth.
  • the formulation can also provide a prolonged action or sustained release by coating or embedding in a polymeric wax or the like.
  • Tissue administration can be carried out by using a liquid dosage unit for subcutaneous / muscular or intravenous injection, for example, in the form of a solution or suspension.
  • a liquid dosage unit for subcutaneous / muscular or intravenous injection for example, in the form of a solution or suspension.
  • a non-toxic liquid carrier suitable for the purpose of injection such as an aqueous or oily medium
  • Non-toxic salts or salt solutions may be added to make the injection solution isotonic.
  • stabilizers, preservatives, emulsifiers and the like can be used together.
  • Rectal administration involves administering the compound to a solid that is soluble or insoluble in low-melting water, for example, polyethylene glycol, cocoa butter, semi-synthetic fats and oils (such as Witepsol, registered trademark), higher esters (such as Milli palmitate). (A still ester) and a suppository produced by dissolving or suspending in a mixture thereof.
  • a solid that is soluble or insoluble in low-melting water for example, polyethylene glycol, cocoa butter, semi-synthetic fats and oils (such as Witepsol, registered trademark), higher esters (such as Milli palmitate).
  • a still ester and a suppository produced by dissolving or suspending in a mixture thereof.
  • ARC239 As a 2B / 2C adrenergic receptor selective antagonist, ARC239 (J. Pharmacol. Exp. Ther. 270: 958-972, 1994).
  • mice fasted overnight C57BL / 6J Jcl, male, 7 weeks old, 4 mice / group
  • mice fasted overnight C57BL / 6J Jcl, male, 7 weeks old, 4 mice / group
  • acetic acid 10 ml / kg
  • Xylazine (2 mg / kg) was administered subcutaneously 10 minutes before administration of acetic acid
  • BL44408 (3 mg / kg) or ARC239 (1 mg / kg) was administered subcutaneously 30 minutes before administration of Xylazine.
  • a significant difference test was performed by Dunnett's multiple comparison test. Table 1 shows the results.
  • the test was performed according to the method described in Neurogastroenterol. Mot., 10: 523-532 (1998).
  • a mouse C57BL / 6J Jcl, male, 7 weeks old, 4 mice / group
  • a force neuration was inserted and fixed 0.5 cm into the proximal colon from the cecum.
  • the other end of the force nucleus was drawn out of the body from the back and the laparotomy was ligated.
  • a marker 5% Chaco-Irzo 10% gum arabic
  • the test was performed according to the method described in Gastroenterology 94: 611-621 (1988).
  • a mouse C57BL / 6J Jcl, male, 7 weeks old, 8 mice / group
  • a 3 nun-diameter tef orifice was introduced into the colon 2 era orally from the anus.
  • Forelimb, Taping was fixed on both shoulders, chest and back, and the time required for ball ejection after awakening was measured.
  • BRL44408 (3 mg / kg) or ARC239 (1 mg / kg) was administered subcutaneously 30 minutes before restraint stress load. Stress was not applied to the normal group, and stress was applied to the control group, and the time required to discharge the ball without drug administration was measured. Significant differences were tested by Dunnett's multiple comparison test. Table 4 shows the results.
  • N represents a normal group.
  • C represents a control group.
  • ⁇ 2 ⁇ -adrenergic receptor selective antagonists do not participate in gastrointestinal motility-modulating effects, which are associated with ⁇ 2-adrenergic receptor antagonism and ⁇ or Q! 2C- adrenergic receptors. Presumably due to body antagonism. Also, as described above, it is known that selective 2-adrenergic receptor antagonists have central and circulatory side effects. Therefore, it does not show 2A-adrenergic receptor antagonism and is selective for ⁇ 2 ⁇ - adrenergic receptor, 3 ⁇ 42C- adrenergic receptor-selective antagonist or Q!
  • 2B / 2C- adrenergic receptor-selective antagonist Antagonists have excellent gastrointestinal motility-modulating effects and have minimal central and circulatory side effects, so they can be used for gastrointestinal motility control and treatment of IBS.
  • Test example 2 Effect on IBS model ( ⁇ 2 ⁇ receptor functional deficient mutant mouse) a 2A receptor functional deficient mutant mouse (C57BL / 6-Adr a 2 a ⁇ " ⁇ , Jackson Laboratory, male, 6-7 weeks old 8) was anesthetized with ether and a Teflon ball with a diameter of 3 mm was inserted into the colon on the side of the mouth 2cra from the anus. The forelimbs, both shoulders, chest and back were fixed by taping, and the ball was discharged after awakening.
  • Yohimbine (3 mg / kg) was administered subcutaneously 30 minutes before the loading of the restraint stress, and no stress was applied to the normal group, but to the control group.
  • the time required for pole excretion without stress was measured by applying stress, and a significant difference test was performed by Dunnett's multiple comparison test, and the results are shown in Table 5.
  • N represents a normal group.
  • C represents a control group.
  • the mixed powder is crushed and made into internal tablets. Industrial availability
  • the pharmaceutical composition of the present invention has a gastrointestinal motility regulating effect and is useful for treating irritable bowel syndrome.

Abstract

L'invention concerne des compositions médicamenteuses contenant comme ingrédient actif un antagoniste sélectif du récepteur adrénergique α2c ou un antagoniste sélectif du récepteur α2c andrénergique. L'invention concerne également son procédé de sélection. L'invention concerne notamment des compositions médicamenteuses destinées au traitement du côlon irritable qui a une excellente action d'amélioration du mouvement intestinal et une sécurité élevée ; et un procédé utile dans sa sélection.
PCT/JP2001/010152 2000-11-22 2001-11-21 Remedes destines a des troubles fonctionnels digestifs et procede de selection WO2002042765A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002224058A AU2002224058A1 (en) 2000-11-22 2001-11-21 Remedies for digestive functional disorder and screening method

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-356040 2000-11-22
JP2000356040A JP2006036636A (ja) 2000-11-22 2000-11-22 消化管機能障害治療剤及びスクリーニング方法

Publications (1)

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WO2002042765A1 true WO2002042765A1 (fr) 2002-05-30

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PCT/JP2001/010152 WO2002042765A1 (fr) 2000-11-22 2001-11-21 Remedes destines a des troubles fonctionnels digestifs et procede de selection

Country Status (3)

Country Link
JP (1) JP2006036636A (fr)
AU (1) AU2002224058A1 (fr)
WO (1) WO2002042765A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6267031A (ja) * 1985-09-18 1987-03-26 メルク　エンド　カムパニ−　インコ−ポレ−テツド 胃腸ぜん動の調節物質としてのα↓２−アドレナリン受容体拮抗物質
JPH06121686A (ja) * 1992-10-12 1994-05-06 Asahi Chem Ind Co Ltd アドレナリンレセプターをコードする遺伝子
WO1999028300A1 (fr) * 1997-12-04 1999-06-10 Allergan Sales, Inc. Derives imidazoles substitues ayant une activite de type agoniste vis a vis des recepteurs adrenergiques alpha 2b ou 2b/2c

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6267031A (ja) * 1985-09-18 1987-03-26 メルク　エンド　カムパニ−　インコ−ポレ−テツド 胃腸ぜん動の調節物質としてのα↓２−アドレナリン受容体拮抗物質
JPH06121686A (ja) * 1992-10-12 1994-05-06 Asahi Chem Ind Co Ltd アドレナリンレセプターをコードする遺伝子
WO1999028300A1 (fr) * 1997-12-04 1999-06-10 Allergan Sales, Inc. Derives imidazoles substitues ayant une activite de type agoniste vis a vis des recepteurs adrenergiques alpha 2b ou 2b/2c

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AU2002224058A1 (en) 2002-06-03

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