Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1997-08-20
1999-09-21
O'Sullivan, Peter
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514347, 514534, 514540, 514562, 514602, 514603, 514605, 546293, 560 9, 560 12, 560 13, 562434, 562435, 562437, 562438, 562442, 562451, 564 86, 564 87, 564 89, 564 90, A61K 3118, A61K 3144
Patent
active
059555050
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
The present invention relates to an agonist (including a potentiator) for glutamate receptors. In detail the present invention relates to an agonist for glutamate receptors comprising a sulfonamide derivative or a pharmaceutically acceptable salt thereof as a effective ingredient.
BACKGROUND OF THE INVENTION
Amino acids which cause excitatory pastsynaptic potential are called as excitatory amino acids (EAA) and such acidic amino acids as L-glutamate, L-aspartate, L-homocysteine acid and quinolinic acid are known as internal substances. It is presumed that neurons using the said amino acids as the transmitters play the central role in the excitatory neurons of the mammalian brain. As a result of the recent rapid progress of the active researches conducted on the mechanism of the EAA transmission the relationship between a wide range of functions of the brain and the disorders of the brain is being unraveled. It has been found that in medicaments causing the disorders very similar to schizophrenia is there is a medical substance which intercepts the actions of the EAA receptors of the type of NMDA(N-methyl-D-aspartate). Accordingly strong attentions have been drawn on a probable participation of the disorders of the EAA transmission in schizophrenia.
As mentioned above the L-glutamate or the L-aspartate, which are amino acids, is a neurotransmitter causing the primary excitotoxic action in the central nervous system. By a number of researches it has been unraveled that the above-mentioned excitatory amino acid relates to a wide range of neurophysiological functions including synaptic transmission, the regulation and the long-term potentiation of neurotransmitters, learning and memory, the flexibility of synaptic generation, ischemic hypoxic disorders and neuronal death, and the cause of several neurodegenerative disorders.
For example, in Alzheimer's or cerebrovascular dementia distinguishing primarily the deterioration of the brain actions the deterioration of glutamatergic transmission is considered to be the cause, and also, the disorder of the glutamatergic transmission is found in schizophrenia.
Glutamate receptors which exist locally in synaps have been classified into the followings according to the receptor's affinity with specific ligand and electrophysiological or neurochemistric actions.
The NMDA (N-methyl-D-aspartate) receptor related to an ion channel characterizing the penetrability of monovalent and divalent cations such as sodium ions and calcium ions and the blockade of magnesium ions.
The AMPA (.alpha.-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor related to an ion channel characterizing the penetrability of monovalent cations such as sodium.
The KA (kainate) receptor which is similar to the AMPA receptor in the ion characteristics but different from the AMPA receptor in both the conductance and the level of desensitization.
(The AMPA receptor and the KA receptor are sometime called collectively as the non-NMDA receptor.)
It is useful to develop potentiating substances of glutamatergic transmission to be used for the prophylactic and medical treatment of the neurodegenerative disorders in the said state of diseases.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide an excellent agonist for glutamate receptors potentiating the actions of glutamate receptors comprising a sulfonamide derivative.
The inventors have studied with utmost effort to develop medical substances potentiating glutamatergic transmission to be used for the prophylactic and medical treatment of the neurodegenerative disorders in the state of diseases and succeeded in finding the potentiation of the response of glutamate receptors by sulfonamide derivatives. And the present invention has been accomplished on the basis of these results.
The invention is an agonist for glutamate receptors comprising a sulfonamide derivative represented by the following formula I ##STR3## group substituted by 1 to 5 members selected from the group consisting of a haloge
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patent: 5677330 (1997-10-01), Abraham et al.
AMPA Receptor Heterogeneity in Rat Hippocampal Neurons Revealed by Differential Sensitivity to Cyclothiazide : Fleck, Mark W. et al. ; Journal of Neurophirosiology vol. 75, No. 6 Jun. 1996 pp. 2322-2333.
Cyclothiazide Modulates AMPA Receptor-Mediated Increases in Intracellular Free Ca.sup.2+ and Mg.sup.2+ in Cultured Neurons From Rat Brain : Hyot Kari R. et al. ; Journal of Neurochemistry vol. 64, No. 5, 1995 pp. 2049-2056.
Cyclothiazide Differentially Modulates Desensitization of .alpha.-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Splice Variants : Partin, Kathryn M. et al. ; Molecular Pharmacology, No. 46, 1994 pp. 129-138.
Chiba Yoshiyuki
Takeo Jiro
Wada Keiji
Yamashita Shinya
Nippon Suisan Kaisha Ltd.
O'Sullivan Peter
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