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WO2005065702A1 - Nouvelle application d'un ligand de la proteine du recepteur semblable a gpr103 - Google Patents

Nouvelle application d'un ligand de la proteine du recepteur semblable a gpr103 Download PDF

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Publication number
WO2005065702A1
WO2005065702A1 PCT/JP2005/000438 JP2005000438W WO2005065702A1 WO 2005065702 A1 WO2005065702 A1 WO 2005065702A1 JP 2005000438 W JP2005000438 W JP 2005000438W WO 2005065702 A1 WO2005065702 A1 WO 2005065702A1
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Prior art keywords
peptide
seq
anxiety
amino acid
symptoms
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Ceased
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PCT/JP2005/000438
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English (en)
Japanese (ja)
Inventor
Shigeru Okuyama
Tatsuya Ohnuki
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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Priority to JP2005516920A priority Critical patent/JP4760377B2/ja
Publication of WO2005065702A1 publication Critical patent/WO2005065702A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
    • G01N33/9466—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals

Definitions

  • the present invention relates to a novel use of polypeptide NPX in the brain. More specifically, the present invention relates to an antidepressant or an anxiolytic using a polypeptide NPX in the brain. Furthermore, the present invention relates to a method for screening for a preventive / therapeutic agent for depression and anxiety neurosis using NPX or NPX and its receptor, GPR103-1 ike receptor protein, and to a substance obtained by the method of screening.
  • Background art
  • BZ benzodiazepine
  • SSR I SSR I and others are used clinically as antidepressants.
  • the discovery and creation of these drugs has led to dramatic advances in drug treatment, but these drugs were not created based on the etiology, resulting in intractable patients and unresponsive symptoms. I have.
  • SSRRI has been reported to be effective for depression as well as panic disorder and obsessive-compulsive disorder, which are symptoms of anxiety (Int. Clin. Psychopharmacol., 6, 5, 1992).
  • BZs are effective for depression, and they are often prescribed clinically. In fact, it is said that 60-70% of depressed patients are accompanied by anxiety in clinical practice, and that 40-90% of anxiety are accompanied by depression (J. Clin. Psychiatry, 54, 75, 1993).
  • anxiety neuroses were classified into panic disorder and generalized anxiety disorder (GAD) according to the diagnostic criteria for mental illness (DSM-III).
  • GAD generalized anxiety disorder
  • DSM-III diagnostic criteria for mental illness
  • CRF CRF
  • POMC POMC
  • CRF has been shown to play a central role in stress responses, such as enhancement of the hypothalamus-pituitary-adrenal system, and has also been implicated in anxiety and depression.
  • Neuropeptides present in the hypothalamus are known to be involved in controlling the activity of the hypothalamus-pituitary-adrenal system, which is closely related to stress response.
  • Many other human brain-derived receptor proteins have been discovered in addition to the above.
  • the GPR103-1 ike receptor is known as one of such receptor proteins (WO 2001/16316).
  • NPX has a high binding affinity to GPR103-1 i ke receptor protein expressed in HEK293 cells.
  • NPX is a peptide synthesized from a gene predicted to encode a protein of unknown function from the human genome sequence, and belongs to the C-terminally amidated RF amide family. It is predicted that the C-terminal will be amidated from the motif of arginine-phenylalanine at the C-terminal, which is processed from the NPX precursor.
  • NPX and GPR 103
  • the ike receptor protein is a peptide that is distributed abundantly in the brain and also in the hypothalamus (The Journal of Biological Chemistry Vo 1, 278, No. 30, Issued of July 25, pp. 27652-27657, 2003) No effect on anxiety has been reported. Furthermore, the relationship with stress response has not been clarified. Furthermore, there are no reports of compounds that target and specifically act on depression anxiety. Disclosure of the invention
  • An object of the present invention is to clarify the relationship between NPX and a disease state and to develop a drug having a novel mechanism of action by using NPX directly or in screening.
  • NPX exhibits an antidepressant effect after a certain period of time after administration. Furthermore, they found that a compound that regulates the binding between NPX and GPR103-1 ike receptor protein, which is an NPX receptor, is effective as a preventive or therapeutic agent for depression or anxiety neurosis.
  • the present invention has been completed based on these findings.
  • An antidepressant or anxiolytic comprising a peptide comprising the amino acid sequence of SEQ ID NO: 1 or 3.
  • a prophylactic or therapeutic agent for depression or anxiety nervous symptoms comprising a peptide having the amino acid sequence of SEQ ID NO: 1 or 3.
  • an agent for preventing or treating depressive symptoms or anxiety symptoms comprising a peptide having symptom-suppressing activity.
  • DNA consisting of the nucleotide sequence of SEQ ID NO: 2 or 4, or a phase thereof
  • An antidepressant or anxiolytic comprising a peptide encoded by DNA that hybridizes to a complement sequence under stringent conditions and having a depressive symptom or anxiety symptom inhibitory activity.
  • a method for suppressing, preventing or treating depression symptoms or anxiety symptoms which comprises administering an effective amount of any one of the following peptides (i) to (iii).
  • amino acids in the amino acid sequence of SEQ ID NO: 1 or 3 are substituted, deleted, added and / or inserted, and have an activity to suppress depression or anxiety.
  • (V) the amino acid sequence of SEQ ID NO: 5 consisting of an amino acid sequence in which one or more amino acids have been substituted, deleted, added, Z or inserted, and from (i) of (9).
  • An agent for preventing or treating depressive symptoms or anxiety nervous symptoms comprising a substance selected by the screening method according to any one of (9) to (11).
  • a method for suppressing, preventing or treating depression or anxiety symptoms comprising administering an effective amount of a substance selected by the screening method according to any one of (9) to (11).
  • a prophylactic or therapeutic agent for depression or anxiety nervous symptoms containing an agonist of a receptor for the peptide having the amino acid sequence of SEQ ID NO: 1 or 3.
  • FIG. 1 shows the measurement results of the mouse tail suspension test in the examples.
  • NPX NPX precursor
  • GPR103-1 ike receptor protein as used herein are known peptides or proteins.
  • the amino acid sequences of NPX, NPX precursor and GPR103-1 ike receptor protein are shown in SEQ ID NOs: 1, 3 and 5, respectively, and the DNA sequence is shown in SEQ ID NOs: 2, 4 and 6, respectively.
  • the antidepressant, the anxiolytic and the preventive or therapeutic agent for depressive symptoms or anxiety symptoms of the present invention include:
  • the number of amino acid mutations and the mutation site in the “amino acid sequence in which one or more amino acids are substituted, deleted, added and / or inserted in the amino acid sequence of SEQ ID NO: 1 or 3” referred to in the present invention are as follows. Although there is no limitation as long as the function of the peptide represented by SEQ ID NO: 1 or 3 is maintained, usually, the homology with the peptide represented by SEQ ID NO: 1 or 3 is about 80% or more, Preferably, the peptide is at least about 90%, more preferably at least about 95%.
  • the number of amino acid mutations is generally 1 to 10, preferably 1 to 8, more preferably about 1 to 5, and particularly preferably 1 to 3.
  • the side chains of the amino acids that constitute the protein are different in hydrophobicity, charge, size, etc., but do not substantially affect the three-dimensional structure (also called three-dimensional structure) of the entire protein.
  • peptides having such highly conserved amino acid substitutions can be used, but are not limited thereto.
  • the amino acid sequence in which one or more amino acids have been substituted, deleted, added and / or inserted in the amino acid sequence described in SEQ ID NO: 1 or 3 is preferably the amino acid sequence described in SEQ ID NO: 1 or 3. It is a peptide functionally equivalent to the peptide consisting of the amino acid sequence.
  • the functionally equivalent peptide refers to the amino acid described in SEQ ID NO: 1 or 3, which has the same biological properties such as receptor-binding activity and cell stimulating activity on receptor-expressing cells. It means that it has a depressive symptom-suppressing action or an anxiety-nerve symptom-suppressing action similar to that of a peptide consisting of an acid sequence.
  • hybridize under stringent conditions means, for example, that the salt concentration is about 19 mM to 40 mM and the temperature is 65 to 75 ° C and 50% formamide when the temperature is not added with formamide. In the presence, it means the degree of hybridization when Southern hybridization is performed under the conditions of 35 to 45 ° C.
  • DNA that hybridizes under stringent conditions include DNAs having a certain degree of homology with the nucleotide sequence of DNA used as a probe, for example, 80% or more, preferably 85% or more, and more preferably Is a DNA having a homology of 90% or more, more preferably 93% or more, particularly preferably 95% or more, and most preferably 98% or more.
  • peptide as used in the present invention means not only an unmodified peptide but also all functionally equivalent peptides, for example, a salt of the peptide, and an amidated or esterified peptide. May be.
  • Peptide salts include physiologically acceptable inorganic acids (eg, hydrochloric acid, phosphoric acid), organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, quinic acid, Examples include salts with malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) or bases (eg, alkali metals). However, especially preferred are physiologically acceptable acid addition salts.
  • physiologically acceptable inorganic acids eg, hydrochloric acid, phosphoric acid
  • organic acids eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, quinic acid
  • examples include salts with malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) or bases (eg, alkali
  • peptide used in the present invention natural peptides derived from humans and other mammals (for example, rats, mice, egrets, chicks, sheep, birds, monkeys, etc.) can be used.
  • the peptide used in the present invention can be produced from human or other mammalian cells or tissues by using a purification method generally available to those skilled in the art. For example, it can be prepared by homogenizing human or other mammalian cells or tissues, extracting them with an acid or the like, and then using ion exchange chromatography or the like.
  • the peptide used in the present invention can be synthesized by a chemical method such as a solid phase method and a liquid phase method which are usually used for peptide synthesis.
  • a chemical method such as a solid phase method and a liquid phase method which are usually used for peptide synthesis.
  • Known protecting groups such as amino groups in the peptide synthesis and condensing agents for the condensation reaction can be used.
  • various commercially available peptide synthesizers can be used. If necessary, the synthesis can be carried out efficiently by protecting and deprotecting the functional groups. Methods for introducing and removing protecting groups are also known to those skilled in the art.
  • a host for example, a suitable host cell such as a mammalian cell or an insect cell
  • a transformant is prepared, and a desired peptide can be isolated and purified as a recombinant peptide from a culture obtained by culturing the transformant.
  • the preparation of the recombinant peptide can be carried out, for example, according to the method described in Current Protocols in Molecular Biology edit. Ausubel et al. (1987) Publish. John Wiley & Sons Section 16.1-16.9.
  • the peptide used in the present invention is an endogenous ligand existing in the living body or a peptide functionally equivalent thereto, it is a safe and low-toxic antidepressant, anxiolytic or depressive symptom or anxiety nervous system. It can be used as an agent for preventing or treating symptoms.
  • the above-mentioned peptide may be used as it is, but usually, a pharmaceutical composition containing the peptide as an active ingredient using one or more pharmaceutically acceptable additives for pharmaceuticals Is preferably produced and administered.
  • the peptide When the peptide is used as a pharmaceutical composition, it can be made into tablets, capsules, elixirs, microcapsules and the like, or as injectables such as sterile solutions and suspensions, according to commonly used means. .
  • the method of administration of the peptide may be oral or parenteral, and the form of parenteral administration is not particularly limited, and may be intravenous, intramuscular, intraperitoneal, or subcutaneous.
  • the dosage of the peptide varies depending on the administration subject, administration method, and the like.
  • about 0.1 to 100 mg per day for a depressed patient (60 kg) is preferable.
  • parenteral administration for example, about 0.01 to 30 mg, preferably about 0.1 to 20 mg, more preferably about 0.1 to 30 mg / day for a depressed patient (60 kg).
  • 10 mg can be injected intravenously.
  • a preventive or therapeutic agent for depressive symptoms or anxiety neurosis which comprises an agonist of a receptor for a peptide consisting of the amino acid sequence of SEQ ID NO: 1 or 3.
  • the peptide comprising the amino acid sequence of SEQ ID NO: 1 or 3 is useful as an agent for preventing or treating depression or anxiety because it has activity to suppress depression or anxiety. It is. Therefore, an agonist of the receptor for the peptide having the same depressive symptom or anxiety nervous symptom inhibitory activity is also useful as an agent for preventing or treating depressive symptoms or anxiety nervous symptoms.
  • the type of agonist of the receptor for the peptide having the amino acid sequence of SEQ ID NO: 1 or 3 is not particularly limited, and may be, for example, a peptide, a peptidomimetic or a low-molecular compound.
  • the above agonists can be selected, for example, by the screening method described in the present specification.
  • the above agonist is used for the prevention or treatment of depressive symptoms or anxiety symptoms.
  • the dosage form, administration method, dosage and the like can be selected in accordance with the case described hereinabove for the peptide.
  • the screening method of the present invention relates to a method for screening for a substance that suppresses depression or anxiety nervous symptoms, and is characterized by using any one of the following peptides (i) to (iii).
  • amino acids in the amino acid sequence of SEQ ID NO: 1 or 3 are substituted, deleted, added and Z or inserted, and have an activity of suppressing depression or anxiety.
  • a protein described in any of the following (i V) to (V i) or a partial peptide of the protein can be used.
  • the number of mutations and mutation sites are not limited as long as the function of the peptide represented by SEQ ID NO: 5 is maintained, but usually the homology is about 80 with the peptide represented by SEQ ID NO: 5.
  • the number of amino acid mutations is generally 1 to 20, preferably 1 to 10, more preferably about 1 to 7, and particularly preferably 1 to 5.
  • specific examples of amino acid substitution include, but are not limited to, the highly conservative substitution described above in the present specification.
  • the amino acid sequence of SEQ ID NO: 5 in which one or more amino acids are substituted, deleted, added, or inserted is preferably a protein consisting of the amino acid sequence of SEQ ID NO: 5. It is a functionally equivalent protein.
  • a functionally equivalent protein means that biological properties such as binding activity to a ligand and signal transduction are equivalent.
  • protein having binding activity differs depending on the measurement method, measurement conditions, and the like.
  • FDSS 600 Haamamatsu Photonitas Means a protein having an EC50 value of 1.0 to 1.5OnM.
  • protein as used in the present invention means not only a naturally-occurring protein but also all functionally equivalent proteins, and further includes salts, amidated or esterified thereof. There may be.
  • the “partial peptide” referred to in the present invention may be a partial peptide of any of the above-mentioned proteins, and is particularly an extracellular portion of the protein of the present invention and a receptor. Those having binding activity are preferred.
  • a natural protein derived from human or other mammals eg, rat, mouse, rabbit, chicken, sheep, chicken, monkey, etc.
  • it may be synthesized by a chemical method such as a solid phase method and a liquid phase method ordinarily used for peptide synthesis, or may be prepared according to a genetic recombination technique. Good.
  • screening method of the present invention include: [1] Screening of a compound that improves the binding activity between the peptide of the present invention and a receptor protein or a partial peptide thereof. And [2] a method for screening a compound that improves the expression level of the peptide of the present invention or its precursor. By such a screening method, a substance capable of suppressing depression symptoms or anxiety symptoms can be selected.
  • Specific examples of the method for screening a substance for improving the binding activity between the peptide and the receptor protein of the present invention include the following methods (a) and (b).
  • a screening method comprising a step of selecting a substance that improves the binding activity in (i) as compared with the binding activity.
  • a substance obtained in this manner can be a candidate substance having a depressive symptom or anxiety nervous symptom suppressing effect.
  • a screening method comprising the steps of: measuring the amount of mRNA encoding the peptide of the present invention; and (ii) comparing the amount of mRNA in the absence of the test substance, and selecting a substance that improves the amount of mRNA in (i). No.
  • a compound that increases the mRNA amount can be a candidate substance having an effect of suppressing depression or anxiety. As described above, it is possible to screen for a substance that suppresses depression symptoms or anxiety symptoms by using the knowledge obtained in the present invention.
  • test substance to be subjected to the screening method of the present invention for example, peptides, proteins, non-peptide compounds, synthetic compounds, fermentation products, cell extracts, plant extracts, animal tissue extracts, etc. are used.
  • the compound may be a novel compound or a known compound.
  • peptide libraries, compound libraries, and the like can also be used.
  • test substance on suppressing depression symptoms or anxiety symptoms can be confirmed using a known method. For example, it can be confirmed by administering orally or parenterally a compound obtained by screening to a depression model animal (eg, mouse) and measuring the immobilization time of the model animal.
  • a depression model animal eg, mouse
  • the substance obtained by the screening method of the present invention has an effect of suppressing depressive symptoms or anxiety symptoms, it can be used as a safe and low-toxicity drug for treatment and prevention.
  • the salt can be used as a medicine.
  • Salts include physiologically acceptable inorganic acids (eg, hydrochloric acid, phosphoric acid), organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid) Oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) or a base (eg, an alkali metal), and a physiologically acceptable acid addition salt is particularly preferable.
  • physiologically acceptable inorganic acids eg, hydrochloric acid, phosphoric acid
  • organic acids eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, mal
  • the above-mentioned substance having the effect of suppressing the symptoms of depression or anxiety may be used as it is, but usually, the substance is formulated using one or more pharmaceutically acceptable additives for pharmaceutical preparations. It is preferable to produce and administer a pharmaceutical composition containing the active ingredient.
  • a pharmaceutical composition containing the active ingredient.
  • the substance can be made into tablets, capsules, elixirs, microcapsules and the like, or as injectables such as sterile solutions and suspensions, according to commonly used means. .
  • the method of administering the substance may be oral or parenteral, and the form of parenteral administration is not particularly limited. Intravenous, intramuscular, intraperitoneal, or subcutaneous administration is performed. be able to.
  • the dose of the substance varies depending on the administration subject, administration method and the like.
  • about 0.1 L 00 mg / day preferably about 1.05 / day for a depressed patient (60 kg) Omg, more preferably about 1.02 Omg.
  • intravenous injection of about 0.0130 mg, preferably about 0.1 20 mg, more preferably about 0.110 mg per day for a depressed patient (60 kg) Can be.
  • mice Male ICR mice (body weight: 25-35 g; Nippon Charlsriver).
  • the tail suspension test was performed with a slight modification of the method reported by Steru et al. (Steru et al., Psychopharmacology, 85, 367-370 (1985)).
  • the mouse was secured by gluing the tail to the gold attribute rod with tape.
  • the rod was fixed at a height of 45 cm from the desk.
  • a tail suspension test was performed for 10 minutes, and the immobilization time for 10 minutes was measured.
  • a test substance prepared by dissolving a predetermined amount of NPX (synthesized by solid phase synthesis) in phosphate-buffered saline containing 0.1% ⁇ serum albumin was administered to mice in the test substance administration group.
  • mice in the control group to which no test substance was administered were each administered intracerebroventricularly with phosphate-buffered saline containing 0.1% serum albumin.
  • mice were lightly anesthetized with halothane, a 27-gauge needle was attached to a Hamilton syringe, and the skull was placed at the intersection of a line drawn 2 mm outside the midline and the front of the base of the ear. And pierced vertically, and injected a drug solution into the ventricle.
  • the administered dose was 5 ⁇ l.
  • a tail suspension test was performed 24 hours after administration. The results are shown in FIG. As is clear from the results shown in FIG.
  • the peptide NPX of the present invention is useful as an agent for preventing or treating depression or anxiety.
  • the effect is exerted after a certain period of time, it is possible to maintain the effect for a long time by combining it with a known preventive or therapeutic drug for depression or anxiety.
  • the compound obtained by the screening method of the present invention is useful as a drug for preventing or treating depression or anxiety.

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Abstract

L'invention concerne l'étude du rapport entre NPX et des troubles pathologiques et la mise au point d'un médicament possédant un nouveau mécanisme fonctionnel qui n'a jamais été observé jusqu'à présent par utilisation directe de NPX ou par criblage à l'aide de NPX. L'invention concerne plus précisément un antidépresseur contenant un peptide comportant une séquence d'acides aminés représentée par SEQ ID NO:1 ou 3.
PCT/JP2005/000438 2004-01-09 2005-01-07 Nouvelle application d'un ligand de la proteine du recepteur semblable a gpr103 Ceased WO2005065702A1 (fr)

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JP2005516920A JP4760377B2 (ja) 2004-01-09 2005-01-07 ＧＰＲ１０３−ｌｉｋｅ受容体蛋白質に対するリガンドの新規用途

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010123150A1 (fr) * 2009-04-22 2010-10-28 Banyu Pharmaceutical Co.,Ltd. Dérivés de 2-aryl imidazoline

Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2003020932A1 (fr) * 2001-09-03 2003-03-13 Takeda Chemical Industries, Ltd. Nouvelles proteines de secretion et adn associe
WO2004022086A1 (fr) * 2002-09-02 2004-03-18 Takeda Pharmaceutical Company Limited Regulateur de secretion d'hormones adrenocorticales
WO2004026904A1 (fr) * 2002-09-17 2004-04-01 Inpharmatica Limited Proteines precurseurs de peptides associes d'amide rf et peptides d'amide rf

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003020932A1 (fr) * 2001-09-03 2003-03-13 Takeda Chemical Industries, Ltd. Nouvelles proteines de secretion et adn associe
WO2004022086A1 (fr) * 2002-09-02 2004-03-18 Takeda Pharmaceutical Company Limited Regulateur de secretion d'hormones adrenocorticales
WO2004026904A1 (fr) * 2002-09-17 2004-04-01 Inpharmatica Limited Proteines precurseurs de peptides associes d'amide rf et peptides d'amide rf

Non-Patent Citations (2)

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Title
FUKUSUMI S. ET AL: "A new peptidic ligand and its receptor regulating adrenal function in rats", J BIOL CHEM, vol. 278, no. 47, 5 September 2003 (2003-09-05), pages 46387 - 46395, XP002267777 *
MEIJER O.C. ET AL: "Elevated basal trough levels of corticosterone suppress hippocampal 5-hydroxytryptamine1A receptor expression in adrenally intact rats: implication for the pathogenesis of depression", NEUROSCIENCE, vol. 80, no. 2, 14 July 1997 (1997-07-14), pages 419 - 426, XP002988245 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010123150A1 (fr) * 2009-04-22 2010-10-28 Banyu Pharmaceutical Co.,Ltd. Dérivés de 2-aryl imidazoline

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