Characterization of the Neurochemical Effects of N-[2-(1-azabicyclo[3,3,0]octan-5-yl)ethyl]2-nitroaniline fumarate (SK-946) as a Cognition Activator
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概要
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The neurochemical effects of SK-946,N-[2-(1-azabicyclo[3,3,0]octan-5-yl)ethyl]2-nitroaniline fumarate, were investigated in an attempt to elucidate cognition activating properties. In rat brain cortical membranes and in cloned human receptors expressed in Sf9 cells, SK-946 had submicromolar affinities for muscarinic receptors with a moderate selectivity for M_1 (m1) sites. Althouth no increase in the antagonist (N-methylscopolamine)/agonist (oxotremorine-M) binding ratio was observed, SK-946 exhibited a partial agonistic effect on receptor-stimulated phosphoinositide hydrolysis in primary cultured rat fetal hippocampal cells. Heterogeneous, reversible and concentration-dependent excitations of the hippocampal neuronal cells treated with SK-946 (10^<-5>-10^<-3> M) were confirmed as increases in cytosolic Ca^<2+> concentrations measured in Fura-PE3 preloaded cells. Furthermore, SK-946 (>10^<-5> M) increased [^3H]myo-inositol uptake into the hippocampal cells. On the other hand, SK-946 had no effect on adenylate cyclase activities in primary cultured rat heart cells, and showed a weak antagonistic effect on carbachol-induced adenylate cyclase inhibition, suggesting that it is an M_2 antagonist. Using in vivo microdialysis, it was found that relatively low concentrations (>10^<-7> M) of SK-946 increased acetylcholine release and decreased choline content in that hippocampal area in rats. These results suggest that SK-946 accelerates muscarinic neuronal transmission in the central nervous system.
- 1998-07-15
著者
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斎藤 徹
Faculty Of Pharmaceutical Sciences Kanazawa University
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Suzuki T
Drug Discovery Research Laboratory Sanwa Kagaku Kenkyusho Co. Ltd.
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鈴木 徳治
千葉大 薬
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Suzuki T
Laboratory Of Biopharmaceutics Faculty Of Pharmaceutical Sciences Chiba University
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Saito T
Research And Development Headquarters Hokurikit Seiyaku Co. Ltd.
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Saito Takako
Research And Development Laboratories Maruho Co. Ltd.
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Suzuki Toshikazu
Discovery Research Laboratory Tanabe Seiyaku Co. Ltd.
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Kanda Kazumi
Pharmaceutical Laboratory Sanwa Kagaku Kenkyusho Co. Ltd.
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Uesaka Hiroshi
Pharmaceutical Laboratory Sanwa Kagaku Kenkyusho Co. Ltd.
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Suzuki T
Research Unit Of Pharmaceutics College Of Pharmacy Nihon University
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Sugihara T
Faculty Of Pharmaceutical Sciences Tokushima Bunri University
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Saito T
Research And Development Laboratories Maruho Co. Ltd.
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SUZUKI Tsunemasa
Pharmaceutical Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd.,
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HIROOKA Kiyotaka
Pharmaceutical Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd.,
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HIROOKA Hiroko
Pharmaceutical Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd.,
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FURUSAWA Kenichi
Pharmaceutical Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd.,
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Suzuki Tsunemasa
Pharmaceutical Laboratory Sanwa Kagaku Kenkyusho Co. Ltd.
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Kanda K
Pharmaceutical Laboratory Sanwa Kagaku Kenkyusho Co. Ltd.
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Furusawa K
Pharmaceutical Laboratory Sanwa Kagaku Kenkyusho Co. Ltd.
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HIROOKA Kiyotaka
Central Research Laboratory, Sanwa Kagaku Kenkyusho, Co., Ltd.,
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Hirooka Kiyotaka
Central Research Laboratory Sanwa Kagaku Kenkyusho Co. Ltd.
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Hirooka Hiroko
Pharmaceutical Laboratory Sanwa Kagaku Kenkyusho Co. Ltd.
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UESAKA Hiroshi
Pharmaceutical Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd.,
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