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WO2006118299A1 - Inhibiteur gpcr - Google Patents

Inhibiteur gpcr Download PDF

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Publication number
WO2006118299A1
WO2006118299A1 PCT/JP2006/309143 JP2006309143W WO2006118299A1 WO 2006118299 A1 WO2006118299 A1 WO 2006118299A1 JP 2006309143 W JP2006309143 W JP 2006309143W WO 2006118299 A1 WO2006118299 A1 WO 2006118299A1
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WIPO (PCT)
Prior art keywords
gpcr
diseases
inhibitor
activity
receptor
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PCT/JP2006/309143
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English (en)
Japanese (ja)
Inventor
Takeaki Ohsu
Sen Takeshita
Yuzuru Eto
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Ajinomoto Co., Inc.
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Priority to JP2007514860A priority Critical patent/JPWO2006118299A1/ja
Publication of WO2006118299A1 publication Critical patent/WO2006118299A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a GPCR inhibitor.
  • GPCR inhibitors are useful as pharmaceuticals for various diseases.
  • G protein-coupled receptors typically share a common structural motif of seven transmembrane helix domains, and contain approximately 800 receptor superfamily. Make it. GPCRs are expressed in cells in a wide range of tissues, and each GPCR responds to a wide variety of specific in vivo ligands such as amines, proteins, peptides, lipids, and nucleic acids, and activates guanine nucleotide-binding proteins. In this way, signals are amplified and transmitted into cells, thereby regulating various physiological functions.
  • GPCR inhibitors or promoters about one-third of the therapeutic agents already on the market are GPCR inhibitors or promoters.
  • Imitrex Imitrex, serotonin receptor inhibitor, headache drug
  • arega Alleg a, histamine receptor inhibitor, allergic disease drug
  • dibrexa Zyprexa, dopamine receptor inhibitor, psychiatric drug
  • Miacalcic Miacalcic calcitonin receptor
  • GPCR inhibitors or promoters that are in the top position in pharmaceutical sales, such as body promoters and osteoporosis drugs.
  • GPCR GPCR ligand serotonin plays a role in processes related to learning and memory, sleep, thermoregulation, mood, motor activity, pain, sexual and aggressive behavior, appetite, neurodegenerative regulation, and biological rhythms. More thoughts. Serotonin receptor inhibitors are expected to improve pathologies such as sexual dysfunction, depression, desire disorders, anxiety, schizophrenia, gastrointestinal disorders, headache, and cardiovascular disorders.
  • GPCRs are medical diseases, neurological diseases, cardiovascular diseases, surgical diseases, neurosurgical diseases, thoracic surgical diseases, orthopedic diseases, obstetrics and gynecological diseases, urological diseases Is an important drug target for the development of therapeutic agents for pediatric diseases, ophthalmic diseases, otolaryngology diseases, dermatological diseases, and dental diseases, and is a safe and pharmacologically superior GPCR inhibitor There is a great need for development.
  • GPCR inhibitors have been developed, but none of them are sufficiently satisfactory in terms of drug efficacy, absorbability, or stability. Of these, the power of safety to the body is particularly important. Most conventional GPCR inhibitors are compounds that do not exist in the body, so they often have unexpected toxicity in addition to their therapeutic effects. Serious side effects could occur if the dose was not tightly controlled.
  • GPCR inhibitors components such as amino acids present in living bodies are expected to be highly safe, but none have been reported as GPCR inhibitors.
  • the following examples of GPCR inhibitors based on amino acid derivatives have been reported as being close to amino acids.
  • the phenyldaricin derivative functions as a metabotropic glutamate receptor inhibitor (Non-patent Document 1)
  • the phenylalanine derivative functions as a cholestokinin receptor inhibitor (Non-patent Document 2).
  • Non-Patent Document 1 J. Neurosci., 1994, 14 (5 Pt 2), 3370-7
  • Non-Patent Document 2 Eur. J. Med. Chem., 2002, 37 (5), 379-89
  • An object of the present invention is to provide a versatile GPCR inhibitor that is highly safe and can be administered orally.
  • the present inventor pays attention to biological components that are present in a living body and have been confirmed to have high safety, and whether these biological components have GPCR inhibitory activity. I did research.
  • serotonin receptors As a representative example of GPCR, serotonin receptors, histamine receptors, and muscarinic receptors are used, and biological component inhibition is performed by an electrophysiological technique using an Xenopus oocyte protein expression system. As a result of evaluating the presence or absence of activity, cysteine, methionine And ornithine were found to have inhibitory activity against serotonin receptors, histamine receptors, and muscarinic receptors, thereby completing the present invention.
  • the present invention is as follows.
  • a GPCR inhibitor having one or more selected strengths of cystine, methionine, and ortin and a derivative comprising these amino acid skeletons.
  • the GPCR inhibitor wherein the GPCR is a receptor selected from a serotonin receptor, a histamine receptor, and a muscarinic receptor.
  • a pharmaceutical product containing the GPCR inhibitor as an active ingredient which is a medical disease, neurological disease, cardiovascular disease, surgical disease, neurosurgical disease, thoracic surgery disease, orthopedic disease
  • a medicine used for the treatment or prevention of surgical diseases obstetrics and gynecological diseases, urological diseases, pediatric diseases, ophthalmic diseases, otolaryngological diseases, dermatological diseases, or dental diseases.
  • FIG. 1 is a graph showing the response current of serotonin to the serotonin receptor.
  • FIG. 2 is a graph showing histamine response current to histamine receptor.
  • FIG. 3 is a graph showing the response current of force rubamilcholine to muscarinic receptors.
  • FIG. 4 is a graph showing inhibition of serotonin receptors by cysteine. The ratio of the response current in the presence of cysteine to the response current in the absence of cysteine is shown on the vertical axis.
  • FIG. 5 shows inhibition of serotonin receptor by methionine. In the absence of methionine The ratio of the response current in the presence of methionine to the response current of is shown on the vertical axis.
  • FIG. 6 is a graph showing inhibition of serotonin receptor by ortin. The ratio of the response current in the presence of ornitine to the response current in the absence of ortin is shown on the vertical axis.
  • FIG. 7 shows inhibition of histamine receptor by cysteine.
  • the ratio of the response current in the presence of cysteine to the response current in the absence of cysteine is shown on the vertical axis.
  • FIG. 8 shows inhibition of mustain receptor by cysteine.
  • the ratio of the response current in the presence of cysteine to the response current in the presence of cysteine is shown on the vertical axis.
  • the GPCR inhibitor of the present invention is one or more selected from cysteine, methionine, and ortin and derivatives including the skeleton of these amino acids.
  • amino acids and derivatives thereof are! And all are L-forms.
  • the amino acid skeleton means a carbon atom constituting the amino acid, a nitrogen atom of an ⁇ -amino group, and a skeleton having cysteine and methionine, which also has a sulfur atom force in addition to these atoms.
  • the derivative containing the amino acid skeleton refers to a compound in which one or two or more hydrogen atoms are substituted with other substituents while maintaining the skeleton.
  • Such derivatives include cystine, homocystine thiolatatane, cysteine, in which a sulfur atom is substituted with an optionally branched alkyl group having 1 to 6 carbon atoms, sulfur atom force carbon numbers 1 to 6 Homocysteine substituted with an alkyl group which may be branched. Further, the sulfur atom or nitrogen atom contained in these derivatives may be optionally oxidized.
  • amino acids or derivatives thereof may be used alone or in combination of any two or more.
  • Cystine, methionine, and ortin have an action of inhibiting a plurality of GPCRs carried out in the evaluation, and can be used as GPCR inhibitors.
  • “Inhibiting GPCR” means that a ligand binds to GPCR and activates a guanine nucleotide-binding protein to transmit a signal, resulting in a series of subsequent signal transduction. It means inhibiting the functional change of cells.
  • the GPCR inhibitor of the present invention can be used as an active ingredient of a pharmaceutical used for the treatment or prevention of various diseases associated with GPCR.
  • the pharmaceutical of the present invention includes pharmaceuticals and quasi drugs.
  • Diseases involving GPCR include medical diseases, neurological diseases, cardiovascular diseases, surgical diseases, neurosurgical diseases, thoracic surgical diseases, orthopedic diseases, obstetrics and gynecology Diseases, urological diseases, pediatric diseases, ophthalmic diseases, otolaryngological diseases, dermatological diseases, and dental diseases.
  • the method for applying the pharmaceutical agent of the present invention containing the GPCR inhibitor is not particularly limited, and oral administration or parenteral administration can be employed.
  • Parenteral administration includes injection or transdermal administration.
  • the pharmaceutical dosage form of the present invention is not particularly limited, and can be administered in the form of a conventional pharmaceutical preparation by mixing with a solid or liquid non-toxic pharmaceutical carrier suitable for the administration method.
  • a solid or liquid non-toxic pharmaceutical carrier suitable for the administration method examples include solid preparations such as tablets, granules, powders and capsules, solutions such as solutions, suspensions and emulsions, and freeze-dried preparations. These preparations can be prepared by conventional means on the preparation.
  • non-toxic pharmaceutical carrier examples include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene alcohol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid.
  • examples include esters, amino acids, gelatin, albumin, water, and physiological saline. If necessary, conventional additives such as stabilizers, wetting agents, emulsifiers, binders, and isotonic agents may be added as appropriate.
  • the effective dose of the pharmaceutical of the present invention is appropriately selected and determined according to the patient's age, weight, symptoms, patient grade, administration route, administration schedule, formulation, strength of inhibitory activity, etc.
  • the total amount of cystine, methionine and ortin and their derivatives is generally about 0.1 lgZ to loogZ per day, preferably about 20 gZ per day.
  • These doses may be administered in several divided doses once a day. Since the amino acids cystine, methionine, and ortin are biological components, they can be taken every day for a long period of time because they are less toxic to the human body. It seems to be excellent in terms of safety.
  • the GPCR inhibitor of the present invention can also be contained in food.
  • the food of the present invention is labeled with a GPCR inhibitory action and can be used for the treatment or prevention of various diseases associated with the GPCR.
  • the food of the present invention can be produced by ordinary methods using ordinary food raw materials except that a GPCR inhibitor is contained.
  • the form of the food is not particularly limited and may be solid or liquid.
  • food includes specified health foods, nutrients, and supplements.
  • the GPCR inhibitor of the present invention can be used as a component of food having an effect of preventing or treating various diseases associated with GPCR.
  • the food is not particularly limited as long as it can stably retain cysteine, methionine, ornithine, or derivatives thereof.
  • the food of the present invention can be produced in accordance with a normal food production method except that cystein, methionine, ortin, or a derivative thereof is added to a food material used for production of a normal food. .
  • the form of the food is not particularly limited, and may be liquid, powder, solid or the like.
  • the GPCR inhibitor of the present invention is an antagonist to the GPCR inhibitor of the present invention, that is, a substance that suppresses the GPCR inhibitory activity of the GPCR inhibitor of the present invention (hereinafter referred to as "GPC R inhibitory activity inhibitor"). Can also be screened. Such a GPCR inhibitory activity inhibitor can be expected to be developed as a therapeutic agent for a disease when GPCR that is inhibited by cystine, methionine, or orthine present in the body is related to the disease. .
  • the GPCR used for screening may be a serotonin receptor, a histamine receptor, or a muscarinic receptor, but any other GPCR may be used as long as it is inhibited by cysteine, methionine, or ortin. May be.
  • the GPCR may be a natural product or a thread-converted product.
  • the origin of GPCR is not particularly limited, and the ability to include GPCRs derived from species such as humans and mice that are mammals, fish, amphibians, and insects that are lower animals. Among these, humans or mice A mold is preferred.
  • the GPCR inhibitory activity inhibitor can be screened, for example, by the following steps, but is not limited to these steps. I) Add the GPCR inhibitor of the present invention, or the GPCR inhibitor of the present invention and a test substance to a GPCR activity measurement system for measuring GPCR activity, and measure the GPCR activity.
  • GPCR activity means that a ligand binds to GPCR and activates a guanine nucleotide-binding protein to transmit a signal, resulting in a series of subsequent signal transmissions. It is a process that leads to changes in cell function.
  • Measurement of GPCR activity is carried out, for example, using a measurement system using cells that express GPCR.
  • the cell may be a cell that endogenously expresses GPCR or a recombinant cell into which a foreign GPC R gene has been introduced.
  • GPCR the type of GPCR, one of the serotonin receptor, histamine receptor and muscarinic receptor mentioned in the examples may be selected, or another GPCR may be used.
  • subtypes of these receptors are not particularly limited.
  • the GPCR activity measurement system is capable of detecting the binding between a ligand and a GPCR when an extra-cellular ligand specific for each GPCR is added to the cell expressing the GPCR, or Any signal can be used without particular limitation as long as it can transmit a detectable signal into the cell in response to the binding between the ligand and the GPCR.
  • the measurement method uses changes in cell metabolism associated with GPCR activity, and the localization or localization of intracellular transmitters. Can be measured using changes in quantity, but any other GPCR evaluation method can be used.
  • the type of measurement is selected to be suitable for the method, and examples include electrophysiological measurement and simultaneous multi-analyte measurement using a multiwell plate for cells.
  • a GPCR inhibitor, or a GPCR inhibitor and a test substance are added to a GPCR activity measurement system for measuring GPCR activity, and GPCR activity is measured.
  • a ligand corresponding to GPCR is added to the GPCR activity measurement system.
  • the amount of ligand added to the GPCR activity measurement system can be determined according to the concentration obtained by examining the working concentration by measuring GPCR activity in advance without adding a GPCR inhibitor.
  • the GPCR inhibitor may be a mixture of cysteine, methionine, and ortin, or any mixture thereof.
  • concentration of the test substance may be arbitrary as long as it does not affect the GPCR activity measurement system itself.
  • the test substance may be a single compound or a mixture or composition containing a plurality of compounds.
  • the ligand, the GPCR inhibitor, and the test substance may be added to the GPCR activity measurement system as long as the GPCR inhibitory activity of the force GPCR inhibitor can be detected at the same time.
  • the GPCR activity when only the GPCR inhibitor is added to the GPCR measurement system and the GPCR activity when the GPCR inhibitor and the test substance are added are compared. Then, a test substance that exhibits high GPCR activity when the test substance is added is selected.
  • the GPCR inhibitory activity inhibitor selected as described above is expected as a therapeutic agent for various diseases associated with the GPCR or a candidate thereof as a new regulator of the GPCR.
  • Serotonin receptor subtype 2A gene, histamine receptor subtype 1 gene, and muscarinic receptor subtype 3 gene were obtained by the PCR method shown below. Oligonucleotide primers used in the PCR method were synthesized based on the DNA sequences of the respective receptors (GenBank accession NM_000621, NM_000861, NM_000740, respectively) registered in NCBI. The primers described in SEQ ID NOs: 1 and 2 are used for the serotonin receptor gene, the primers described in SEQ ID NOs: 3 and 4 are used for the muscarinic receptor gene, and the primers described in SEQ ID NOs: 5 and 6 are used for the histamine receptor gene. used.
  • PCR was performed under the following conditions using Pfu ultra DNA Polymerase (Stratagene) using cDNA derived from human brain (Clontech) as a material. After 3 minutes at 94 ° C, 30 seconds at 94 ° C, 30 seconds at 55 ° C, and 2 minutes at 72 ° C were repeated 35 times, and a reaction was carried out at 72 ° C for 7 minutes. The presence and size of the amplified product was confirmed by agarose electrophoresis.
  • Plasmid vector pBR322 was digested with restriction enzyme EcoRV (Takara). Each gene fragment amplified by PCR was ligated to the cleavage site using Ligation Kit (Promega). The Eshierihia 'coli DH5 a strain with the reaction solution was transformed, PCR amplification products were selected transformants carrying the Kuroyungu plasmid. It was confirmed by DNA nucleotide sequence analysis that each PCR amplification product was a serotonin receptor gene, a histamine receptor gene, or a muscarinic receptor gene. These recombinant plasmids were used as cages, and cDNAs for each receptor gene were prepared using a cRNA preparation kit (Ambion).
  • amino acid samples special grades of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenyllauranin, proline, serine, threonine, tryptophan, Twenty-two types were used: tyrosine, norin, ortin, and taurine. Each amino acid was dissolved in glutamic acid, aspartic acid, tryptophan in 25 mM, and the others in lOO mM in the following thread buffer. NaCl 96mM, KC1 2mM, MgCl ImM, CaCl 1.8m
  • the buffer solution was also used as a solution for preparing Xenopus oocytes and a ligand solution.
  • the medium for culturing the oocyte contains 2 mM pyruvic acid and 10 mM in the same buffer.
  • an Xenopus oocyte expression system was used as a method for measuring GPCR activity and GPCR inhibition.
  • intracellular Ca ions increase.
  • the Ca concentration ion-dependent C1 channel opens, and the intracellular current value changes as an ionic current.
  • Xenopus laevis An abdomen of Xenopus laevis was incised and the egg mass was taken out, and then treated with a 1% collagenase solution at 20 ° C. for 2 hours to disperse the oocytes to obtain oocytes.
  • 50 nl of receptor cRNA solution (1 ⁇ g Z 1) or 50 nl of sterile water was introduced into each oocyte.
  • the oocytes were cultured in a petri dish having a diameter of 5 cm in 10 ml of the above medium at 18 ° C. for 2 to 3 days.
  • Electrophysiological measurement was performed by using an amplifier Geneclamp (Axon Inc.) and recording software AX O S CO pe9.0 (Ax O n , Inc.). After incubation, the oocytes were fixed at -70 mV by the two-electrode membrane potential fixation method, and the intracellular current via Ca concentration ion-dependent C1 ions was measured. The maximum value of the intracellular current was taken as the response current value.
  • a ligand solution having a final concentration shown in parentheses below was added to each oocyte with a fixed membrane potential.
  • Each ligand was obtained from Nacalai Testa.
  • the presence or absence of inhibitory activity of various amino acids on serotonin receptors was evaluated as follows. Using the method described in Example 3, an oocyte into which the serotonin receptor gene was introduced was prepared, and the membrane potential was fixed at ⁇ 70 mV by the two-electrode membrane potential fixing method. After adding one amino acid to each oocyte with fixed membrane potential, serotonin ( ⁇ ) was added to measure the Ca ion concentration-dependent C1 current response.
  • amino acids tested and their final concentrations are as follows: Alanine (lOmM), arginine (lOmM), asparagine (lOmM), aspartic acid (lOmM), cysteine (lOmM), glutamine (lOmM), glutamic acid (lOmM), glycine (lOmM), histidine (lOml, m ), Mouth isine (10 mM), lysine (lOmM), methen (lOmM), ferulanin (lOmM), mouth phosphorus (lOmM), serine (10 mM), threonine (10 mM), tryptophan (lOmM) ), Tyrosin (lOmM), parin (lOmM), or-tin (lOmM), taurine (10 mM).
  • the presence or absence of inhibitory activity was expressed as a ratio obtained by dividing the response current value of the ligand solution in the presence of the amino acid solution by the response current value when the ligand solution alone was added. That is, the response current ratio in the absence of amino acids is 1, and when the amino acid has inhibitory activity, the response current ratio is smaller than 1.
  • the current response specific force against serotonin was reduced to 0.6 or less, it was judged as having inhibitory activity.
  • serotonin receptor inhibitory activity was observed only when cysteine, methionine, or ortin was added. For amino acids other than cystine, methionine, and oroutine, no inhibitory activity was observed (Table 1).
  • Example 6 Concentration-dependent evaluation of serotonin receptor inhibitory activity of three types of amino acids
  • concentration-dependent evaluation of the inhibitory activity against serotonin receptors was evaluated by the following method. I went there. Using the method described in Example 3, an oocyte into which the serotonin receptor gene was introduced was prepared, and the membrane potential was fixed at 70 mV by the two-electrode membrane potential fixation method. Three kinds of amino acids to be evaluated for inhibitory activity were added to oocytes with fixed membrane potential, and then serotonin ( ⁇ ) was added to measure the Ca ion concentration-dependent C1 current response. . Each amino acid concentration was determined at the following three points.
  • the inhibitory activity of cysteine against the histamine receptor and the muscarinic receptor was evaluated by the following method. Using the method described in Example 3, an oocyte into which the histamine receptor gene or muscarinic receptor gene was introduced was prepared, and the membrane potential was fixed at -70 mV by the two-electrode membrane potential fixation method. After adding cystine (lmM, 3 mM, 5 mM) to the oocyte fixed with membrane potential, histamine ( ⁇ ) or force rubamylcholine (30 nM) was added, and the Ca ion concentration-dependent C1 current response was measured. The results are shown in Figs. As a result, when cysteine was added, a concentration-dependent inhibitory activity against histamine receptor and muscarinic receptor was observed, similar to serotonin receptor.
  • the present invention provides a highly safe and versatile GPCR inhibitor.

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Abstract

L’invention concerne un ou plusieurs éléments choisis parmi la cystéine, la méthionine, l’ornithine et les dérivés contenant un squelette de n’importe lequel de ces acides aminés sont utilisés comme inhibiteurs de GPCR tels qu’un récepteur de sérotonine, un récepteur d’histamine ou un récepteur muscarinique.
PCT/JP2006/309143 2005-05-02 2006-05-02 Inhibiteur gpcr WO2006118299A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
JP2007031375A (ja) * 2005-07-28 2007-02-08 Kyowa Hakko Kogyo Co Ltd 肌質改善用経口剤

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WO2003011056A1 (fr) * 2001-07-31 2003-02-13 Ajinomoto Co., Inc. Compositions alimentaires ergogeniques

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