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EXCITATORY CHEMICAL MEDIATOR AND METHOD FOR SCREENING THEREOF UPDATE コモンズ 新技術説明会

外国特許コード F100002332
掲載日 2010年12月14日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2009JP055208
国際公開番号 WO 2009116546
国際出願日 平成21年3月17日(2009.3.17)
国際公開日 平成21年9月24日(2009.9.24)
優先権データ
  • 特願2008-070207 (2008.3.18) JP
発明の名称 (英語) EXCITATORY CHEMICAL MEDIATOR AND METHOD FOR SCREENING THEREOF UPDATE コモンズ 新技術説明会
発明の概要(英語) Disclosed is an inhibitor which can inhibit at least two vesicular neurotransmitter transporters for excitatory neurotransmitters under a chloride concentration included in physiological conditions. Also disclosed is a novel method for the screening of the inhibitor. The inhibitor is useful for the treatment of epilepsy, inflammations, tremor, pain, hypertension, ischemia, Parkinson's disease, Alzheimer's disease, osteopetrosis, osteoporosis or the like. Further disclosed is a method for the screening of a substance capable of activating a suppressed vesicular neurotransmitter transporter.
従来技術、競合技術の概要(英語) BACKGROUND ART
Neurotransmitter is, the pre-synaptic cells released from the (presynaptic cells), across the synapse on the post-synaptic cell (the postsynaptic cell) stimulate or inhibit the specific chemical substance. Neurotransmitter is, produced in neurons that is released from the presynaptic endings, act directly on the postsynaptic membrane. This effect is caused by a target cell by response reactions, produce electrical excitation or inhibition. Produce electrical excitement excitatory neurotransmitters is referred to as a transfer material, to produce electrically suppressed inhibitory neurotransmitters called neurotransmitters. Neurotransmitter is produced in neurons, preganglionic neurons synaptic vesicle cells present in the synaptic vesicles by neurotransmitter transporter stored, released into the synaptic cleft by exocytosis, postsynaptic cells present on the cell surface receptor binding on the other hand, the pre-synaptic endings or present in the cell membrane of glial cells recovered by the neurotransmitter transporter.
Is the kinetics of this series of neurotransmitters, neurotransmitter present in the synaptic vesicle transporter (vesicular neurotransmitter transporter or a vesicular transporter called) and the pre-synaptic endings, glial cells of the neurotransmitter transporter present in the cell membrane (plasma membrane-type transporter) is involved in the, these transporters are 2 types of neuronal neurotransmitter molecule different in structure and function.
(Epilepsy) is epilepsy, seizures and excessive discharge of neurons of the brain dysfunction is a disease characterized by, typically, is a disease involving modulation of consciousness. Stroke is elementary or composite action and is limited to the disorders, the left and the development of systemic vasospasm. Is the clinical manifestation of seizures, generalized convulsions or local vasospasm to abnormality in the behavior of the complex, the instantaneous stroke vary from disturbance of consciousness. Of the various categories is the clinical manifestation of these is. Type of seizures and descriptive term is standardized, the completely is not unified.
As described above, epilepsy seizures and excessive discharge of neurons of the brain dysfunction features of, as a function of the anti-epileptic drugs, excitatory chemical reduce signaling on the other hand, by increasing the inhibitory chemical transfer can be considered.
For example, known anti-epileptic drugs in the effect of valproic acid, possibly in the brain to increase the concentration of inhibitory GABA is believed to make a. Almost all type of epilepsy valproic acid is considered to be effective, a dose-dependent extinguishers and adverse effects on liver and, in addition, in the teratogenicity. Na channel due to the suppression of neural excitability in a drug that inhibits the phenytoin are known, nystagmus, dysarthria, ataxia, vertigo, double vision, somnolence, abnormal behavior, cognitive impairment, hypersensitivity, rash, hirsutism, gingival growth, Osteomalacia, and, anemias known side effects. For example the existing anti-epileptic drugs and the problems of side effects, and combination therapies are used to only increase the side effects, usually, in a single agent TDM (therapeutic effect or side effects related to a variety of factors while monitoring to each patient can be personalized drug administration) of using the optimum usually intended to be used.
Reduction of excitatory chemical transfer for development of anti-epileptic drugs through, neurotransmitter transporter activity regulating agent if targeting, the pre-synaptic endings, glial cells of the excitatory neurotransmitter present in the cell membrane specific neurotransmitter transporter (cell membrane-type neurotransmitter transporter) activator, or, synaptic vesicle present excitatory neurotransmitter specific neurotransmitter transporter (vesicular neurotransmitter transporter) can be assumed to be an inhibitor of. This is because, cell membrane-type activated neurotransmitter transporter, synaptic cleft excitatory neurotransmitter released by promoting the clearance of the excitatory chemical transfer is expected to decrease is reasonable. In addition, vesicular neurotransmitter transporter inhibition, synaptic vesicle stored in the decrease in the amount of excitatory neurotransmitters and, as a result, a decrease in excitatory chemical transfer is reasonably is expected.
However, there are a plurality of excitatory neurotransmitters from, in epilepsy, a plurality of excitatory neurotransmitter is thought to be involved. For example, glia cells will be associated with diseases such as epilepsy is known and, then, glial cells, such as glutamic ATP secreting excitatory neurotransmitter is known, by inhibiting its secretion, can be expected efficacy in treating these diseases is considered to be a (non-patent document 5-13). Therefore, as anti-epileptic drugs candidate compounds, a plurality of types of excitatory neurotransmitters inhibits the action of the compound is obtained.
On the other hand, neurotransmitter transporter, vesicular determine whether or not the cell membrane regardless of whether the, with respect to the various types of excitatory neurotransmitters which have a specificity for, neurotransmitter transporter as a target for the anti-epileptic drugs is developed, a wide variety of neurotransmitter transporter target must be considered.
Vesicular glutamate transporter have been studied for the inhibitor for the (non-patent document 1) although, any of which may be, glutamic acid transporter and a compound having a structure similar, vesicular neurotransmitter transporter protein to bind irreversibly to dyes with respect to the compound. Vesicular glutamate transporter is a compound having a structure similar to, a plurality of types of vesicular neurotransmitter transporter is believed to inhibit. In addition, vesicular neurotransmitter transporter protein dye that binds irreversibly to this compound was identified as the center, vesicular neurotransmitter transporter serpans and, as a result, side effects that cannot be overlooked are expected.
Vesicular glutamate transporter, chloride ions and is known to be the demand of the (non-patent document 2), glutamic acid -3 - methyl valerate 2 - keto vesicular transporter chloride ions change requirement also known (non-patent document 3 and 4). However, methyl valerate 2 - keto acid is -3 -, the inhibitory effect of the vesicular glutamate transporter is very small and, therefore, as an inhibitor of vesicular glutamate transporter is a practical value is not recognized. Keto acid methyl valerate 2 - -3 - since the body by the enzyme deficiencies-gene is accumulate, neurotoxicity is reported (non-patent document 3 and 4). For this reason, methyl valerate -3-2 - keto acid is, for the treatment of diseases such as epilepsy instead of being useful, can be considered to act as a neurotoxin.
At the present time, neurotransmitter transporter (in particular, vesicular neurotransmitter transporter) structure and function, as well as inhibitors are described in, knowledge can not sufficiently. Therefore, a wide variety of neurotransmitter transporter activity regulating agent directed to the development of difficulty is expected.
Such difficulty even though it is foreseen that, excitatory neurotransmitter molecule that is directly related to neurotransmitter transporter as a target for anti-epileptic drugs may bind reversibly, with fewer side effects are expected from the attractive advantages for, a wide variety of neurotransmitter transporter activity regulating agent of interest (for example, excitatory chemical inhibitor) development is demanded. In addition, an agent that activates the suppressed the development of neurons are also demanded.
Excitatory chemical transduction inhibitor is, in addition to epilepsy, inflammation, tremor, pain, hypertension, ischemia, Parkinson's disease, Alzheimer's disease, marble disease, and, for the treatment of a disease of such coarse/bone, prevention, and/or prognosis is believed to be useful.
Of this application as prior art document information related to the invention, is the following.
Thompson, C. M.Et al., "Inhibitorof the glutamate vesiculartransporter (VGLUT) ", Curr. Med. Chem. 12,2041-2056 (2005)
Juge N, YoshidaY, Yatsushiro S, Omote H, Moriyama Y.、"Vesicularglutamate transportercontains two independent transport machineries."、JBiol Chem. 2006 Dec22;281 (51) :39499-506.
Tavares RG et al., "Inhibitionof glutamate uptake into synapticvesicles of rat brain by the metabolitesaccumulating in maple syrup urinedisease.", J Neurol Sci. 2000 Dec1; 181 (1-2): 44-9
Marcelo Reis,Mariana Farage, Herman Wolosker、"Chloride-dependentinhibition ofvesicular glutamate uptake by alpha-keto acids accumulated inmaple syrup urine
Bekar L et al., (2008) Adenosine is crucial for deep brainstimulation-mediated attenuation oftremor. Nature Med. 14, 75-80.
Tian G-F etal., An astrocytic basis of epilepsy. Nature Med. 2005,973-981.
noue K et al., (2007) The role of nucleotides in the neuron-gliacommunication responsible forthe brain functions. J. Neurochem. 102, 1447-1458.
INedergaard Mand Dirnagl U. (2005) Role of glical cells in cerebralischemia. Glia 50,281-286.
Fields RD andBurnstock G. (2006) Purinergic signaling in neuron-gliainteractions. NatureNeuroscience 7, 423-436.
Tian G-F etal., An astrocytic basis of epilepsy. Nature Med. 2005,973-981.
Walts E (2007) Epilepsy controlled by low-carb diets effect on brainchannels. Nature Med. 13,516-517.
Freeman J etal., (2006) The ketogenic diet: From molecularmechanisms to clinical effects.Epilepsy Res. 68, 145-180 .
AL etal. Hartman, (2007) The neuropharmacology of the ketogenicdiet. Pediatr Neurol 36,281-292 .
  • 出願人(英語)
  • ※2012年7月以前掲載分については米国以外のすべての指定国
  • National University Corporation Okayama University
  • 発明者(英語)
  • MORIYAMA, Yoshinori
  • OMOTE, Hiroshi
  • JUGE, Narinobu
国際特許分類(IPC)
指定国 National States: AE AG AL AM AO AT AU AZ BA BB BG BH BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PG PH PL PT RO RS RU SC SD SE SG SK SL SM ST SV SY TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ MD RU TJ TM
EPO: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

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