Pharmacological Characterization of RS-1259, an Orally Active Dual Inhibitor of Acetylcholinesterase and Serotonin Transporter, in Rodents : Possible Treatment of Alzheimer's Disease
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概要
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A dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT), RS-1259 (4-[1S)-methylamino-3-(4-nitrophenoxy)]propylphenyl N,N-dimethylcarbamate (fumaric acid)1/2salt), was newly synthesized. RS-1259 simultaneously inhibited AChE and SERT in the brain following an oral administration in mice and rats. Actual simultaneous elevation of extracellular levels of 5-HT and ACh in the rat hippocampus was confirmed by microdialysis. The compound was as effective as SERT inhibitors such as fluoxetine and fluvoxamine in a 5-hydroxytryptophan-enhancing test in mice. Spatial memory deficits in the two-platform task of a water maze in aged rats were ameliorated by RS-1259 as well as donepezil. Both RS-1259 and donepezil increased the awake episodes in the daytime electroencephalogram of rats. Although RS-1259 was weaker than donepezil in enhancing central cholinergic transmission, as observed by ACh elevation in the hippocampus and memory enhancement in aged rats, the efficacy of RS-1259 on the consciousness level, which reflects the whole activity in the brain, was almost the same as that of donepezil. These results suggest that both cholinergic and serotonergic systems are involved in maintaining brain arousal and that a dual inhibitor of AChE and SERT may be useful for the treatment of cognitive disorders associated with reduced brain activity such as in Alzheimer’s disease.
- 社団法人 日本薬理学会の論文
- 2003-09-01
著者
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KOGEN Hiroshi
Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd.
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TAGO Keiko
Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd.
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Hara Takao
Neuroscience And Immunology Research Laboratories Sankyo Co. Ltd.
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Yamada Naho
Exploratory Chemical Research Laboratories Sankyo Co. Ltd.
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Naruto Shunji
Exploratory Chemical Research Laboratories Sankyo Co. Ltd.
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Kaneko Tsugio
Neuroscience And Immunology Research Laboratories Sankyo Co. Ltd.
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Tago Keiko
Exploratory Chemistry Research Laboratories Sankyo Co. Ltd.
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Yamazaki Reina
Neuroscience And Immunology Research Laboratories Sankyo Co. Ltd.
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ABE Yasuyuki
Neuroscience and Immunology Research Laboratories Sankyo Co., Ltd.
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AOYAGI Atsushi
Neuroscience and Immunology Research Laboratories Sankyo Co., Ltd.
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ABE Kazumi
Neuroscience and Immunology Research Laboratories Sankyo Co., Ltd.
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KUMAGAE Yoshihiro
Neuroscience and Immunology Research Laboratories Sankyo Co., Ltd.
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KOYAMA Kazuo
Exploratory Chemical Research Laboratories, Sankyo Co., Ltd.
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MARUMOTO Shinji
Exploratory Chemical Research Laboratories, Sankyo Co., Ltd.
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TODA Narihiro
Exploratory Chemical Research Laboratories, Sankyo Co., Ltd.
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TAKAMI Kazuko
Exploratory Chemical Research Laboratories, Sankyo Co., Ltd.
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ORI Mayuko
Exploratory Chemical Research Laboratories, Sankyo Co., Ltd.
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Kogen Hiroshi
Exploratory Chemistry Research Laboratories Sankyo Co. Ltd.
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Ori Mayuko
Exploratory Chemical Research Laboratories Sankyo Co. Ltd.
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Abe Kazumi
Neuroscience And Immunology Research Laboratories Sankyo Co. Ltd.
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Koyama Kazuo
Exploratory Chemical Research Laboratories Sankyo Co. Ltd.
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Takami Kazuko
Exploratory Chemical Research Laboratories Sankyo Co. Ltd.
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Aoyagi Atsushi
Neuroscience And Immunology Research Laboratories Sankyo Co. Ltd.
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Kumagae Yoshihiro
Neuroscience And Immunology Research Laboratories Sankyo Co. Ltd.
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Abe Yasuyuki
Neuroscience And Immunology Research Laboratories Sankyo Co. Ltd.
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Marumoto Shinji
Exploratory Chemical Research Laboratories Sankyo Co. Ltd.
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Kogen Hiroshi
Exploratory Chemical Research Laboratories, Sankyo Co., Ltd.
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Tago Keiko
Exploratory Chemical Research Laboratories, Sankyo Co., Ltd.
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- Pharmacological Characterization of RS-1259, an Orally Active Dual Inhibitor of Acetylcholinesterase and Serotonin Transporter, in Rodents : Possible Treatment of Alzheimer's Disease
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