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Zhong Chen - One of the best experts on this subject based on the ideXlab platform.
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effect of 3 1 phenylmethyl 4 piperidinyl 1 2 3 4 5 tetrahydro 1h 1 benzazepin 8 yl 1 propanone fumarate a novel acetylcholinesterase inhibitor on spatial cognitive impairment induced by chronic cerebral hypoperfusion in rats
Neuroscience Letters, 2002Co-Authors: Zhong Chen, Kazuhiko Yanai, Yu Wen Huang, Erqing WeiAbstract:It is of interest whether the acetylcholinesterase inhibitor, 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1h-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), can improve cognitive impairment caused by chronic cerebral ischemia in rats. Two weeks after four-vessel occlusion, apparent impairments of spatial retrieval memory were observed in the Morris water maze. Both TAK-147 at doses of 0.1, 0.3 and 1.0 mg/kg and donepezil at doses of 0.3 and 1.0 mg/kg significantly ameliorated ischemia-induced memory deficits dose-dependently, but tacrine had no appreciable effect. Furthermore, we demonstrate that the intensity of staining by 2,3,5-triphenyltetrazolium in the hippocampal and cortical slices was significantly decreased by ischemia (10 min anoxia/aglycemia), and that it was also significantly restored by treatment with TAK-147 and donepezil.
Erqing Wei - One of the best experts on this subject based on the ideXlab platform.
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effect of 3 1 phenylmethyl 4 piperidinyl 1 2 3 4 5 tetrahydro 1h 1 benzazepin 8 yl 1 propanone fumarate a novel acetylcholinesterase inhibitor on spatial cognitive impairment induced by chronic cerebral hypoperfusion in rats
Neuroscience Letters, 2002Co-Authors: Zhong Chen, Kazuhiko Yanai, Yu Wen Huang, Erqing WeiAbstract:It is of interest whether the acetylcholinesterase inhibitor, 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1h-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), can improve cognitive impairment caused by chronic cerebral ischemia in rats. Two weeks after four-vessel occlusion, apparent impairments of spatial retrieval memory were observed in the Morris water maze. Both TAK-147 at doses of 0.1, 0.3 and 1.0 mg/kg and donepezil at doses of 0.3 and 1.0 mg/kg significantly ameliorated ischemia-induced memory deficits dose-dependently, but tacrine had no appreciable effect. Furthermore, we demonstrate that the intensity of staining by 2,3,5-triphenyltetrazolium in the hippocampal and cortical slices was significantly decreased by ischemia (10 min anoxia/aglycemia), and that it was also significantly restored by treatment with TAK-147 and donepezil.
Masaomi Miyamoto - One of the best experts on this subject based on the ideXlab platform.
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neurochemical effects of 3 1 phenylmethyl 4 piperidinyl 1 2 3 4 5 tetrahydro 1h 1 benzazepin 8 yl 1 propanone fumarate tak 147 a novel acetylcholinesterase inhibitor in rats
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Keisuke Hirai, Koki Kato, Takahiro Nakayama, Hitomi Hayako, Yuji Ishihara, Giichi Goto, Masaomi MiyamotoAbstract:We examined the neurochemical effects of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1h-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), a novel acetylcholinesterase (AChE) inhibitor in vitro and in vivo . TAK-147 showed a potent and reversible inhibition of AChE activity in homogenates of the rat cerebral cortex (IC50 = 51.2 nM), and was 3.0- and 2.4-fold more potent than tacrine and physostigmine, respectively. By contrast, TAK-147 was the least potent inhibitor of butyrylcholinesterase activity in rat plasma (IC50 = 23,500 nM). Tacrine and physostigmine inhibited butyrylcholinesterase activity potently and nonselectively. TAK-147 showed a moderate inhibition of muscarinic M1 and M2 receptor binding with Ki values of 234 and 340 nM, respectively. TAK-147 showed very weak or no inhibition of high-affinity choline uptake, nicotinic receptor binding and choline acetyltransferase activity. In ex vivo experiments, oral administration of TAK-147 at doses ranging from 1 to 10 mg/kg induced a statistically significant and dose-dependent decrease in AChE activity in the cerebral cortex. Of the monoaminergic systems, TAK-147 moderately inhibited uptake of noradrenaline and serotonin with IC50values of 4020 and 1350 nM, respectively. TAK-147 also inhibited ligand binding at alpha -1, alpha -2 and serotonin 2 receptors with Ki values of 324, 2330 and 3510 nM, respectively, whereas it showed only weak activities on D1, D2 and serotonin 1A receptor bindings. Oral administration of TAK-147 (3 mg/kg) significantly accelerated the turnover rates of dopamine, noradrenaline and serotonin in the rat brain. These results suggest that TAK-147 activates the central cholinergic system by specific inhibition of AChE activity without affecting peripheral butyrylcholinesterase activity, and that TAK-147 also moderately activates the monoaminergic systems.
Katsumi Itoh - One of the best experts on this subject based on the ideXlab platform.
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optically active antifungal azoles xiii synthesis of stereoisomers and metabolites of 1 1r 2r 2 2 4 difluorophenyl 2 hydroxy 1 methyl 3 1h 1 2 4 triazol 1 yl propyl 3 4 1h 1 tetrazolyl phenyl 2 imidazolidinone tak 456
Chemical & Pharmaceutical Bulletin, 2001Co-Authors: Takashi Ichikawa, Masami Yamada, Masashi Yamaguchi, Tomoyuki Kitazaki, Yoshihiro Matsushita, Keiko Higashikawa, Katsumi ItohAbstract:1-[(1R, 2R)-2-(2, 4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1h-1, 2, 4-triazol-1-yl)propyl]-3-[4-(1h-1-tetrazolyl)phenyl]-2-imidazolidinone [(1R, 2R)-1: TAK-456] is a new antifungal agent selected as a candidate for clinical trials. The three stereoisomers [(1S, 2R)-, (1S, 2S)- and (1R, 2S)-1] of this compound were prepared as authentic samples to determine the enantiomeric and diastereomeric purity of TAK-456 as well as to compare their in vitro antifungal activity. Pharmacokinetic studies of TAK-456 using rats identified the existence of metabolites in the liver homogenate. The structures of the major metabolites were assigned as 4-hydroxy-2-imidazolidinone (3) and/or 5-hydroxy-2-imidazolidinone (4), based on HPLC and LC/MS/MS analyses. These hydroxylated compounds, 3 and 4, were prepared by reduction of the corresponding imidazolidinediones, 11 and 12, and confirmed to be identical to the metabolites by HPLC. In vitro antifungal activities of the three stereoisomers and the synthesized metabolites were considerably weaker than TAK-456.
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optically active antifungal azoles xii synthesis and antifungal activity of the water soluble prodrugs of 1 1r 2r 2 2 4 difluorophenyl 2 hydroxy 1 methyl 3 1h 1 2 4 triazol 1 yl propyl 3 4 1h 1 tetrazolyl phenyl 2 imidazolidinone
Chemical & Pharmaceutical Bulletin, 2001Co-Authors: Takashi Ichikawa, Masami Yamada, Masashi Yamaguchi, Tomoyuki Kitazaki, Yoshihiro Matsushita, Ryogo Hayashi, Yutaka Kiyota, Kenji Okonogi, Katsumi ItohAbstract:1-[(1R, 2R)-2-(2, 4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1h-1, 2, 4-triazol-1-yl)propyl]-3-[4-(1h-1-tetrazolyl)phenyl]-2-imidazolidinone (1: TAK-456) was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, the quaternary triazolium salts 2 were designed as water-soluble prodrugs. Among the prodrugs prepared, 4-acetoxymethyl-1-[(2R, 3R)-2-(2, 4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1h-1-terazolyl)phenyl]-1-imidazolidinyl]butyl]-1h-1, 2, 4-triazolium chloride (2a: TAK-457) was selected as an injectable candidate for clinical trials based on the results of evaluations on solubility, stability, hemolytic effect and in vivo antifungal activities.
Keisuke Hirai - One of the best experts on this subject based on the ideXlab platform.
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neurochemical effects of 3 1 phenylmethyl 4 piperidinyl 1 2 3 4 5 tetrahydro 1h 1 benzazepin 8 yl 1 propanone fumarate tak 147 a novel acetylcholinesterase inhibitor in rats
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Keisuke Hirai, Koki Kato, Takahiro Nakayama, Hitomi Hayako, Yuji Ishihara, Giichi Goto, Masaomi MiyamotoAbstract:We examined the neurochemical effects of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1h-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), a novel acetylcholinesterase (AChE) inhibitor in vitro and in vivo . TAK-147 showed a potent and reversible inhibition of AChE activity in homogenates of the rat cerebral cortex (IC50 = 51.2 nM), and was 3.0- and 2.4-fold more potent than tacrine and physostigmine, respectively. By contrast, TAK-147 was the least potent inhibitor of butyrylcholinesterase activity in rat plasma (IC50 = 23,500 nM). Tacrine and physostigmine inhibited butyrylcholinesterase activity potently and nonselectively. TAK-147 showed a moderate inhibition of muscarinic M1 and M2 receptor binding with Ki values of 234 and 340 nM, respectively. TAK-147 showed very weak or no inhibition of high-affinity choline uptake, nicotinic receptor binding and choline acetyltransferase activity. In ex vivo experiments, oral administration of TAK-147 at doses ranging from 1 to 10 mg/kg induced a statistically significant and dose-dependent decrease in AChE activity in the cerebral cortex. Of the monoaminergic systems, TAK-147 moderately inhibited uptake of noradrenaline and serotonin with IC50values of 4020 and 1350 nM, respectively. TAK-147 also inhibited ligand binding at alpha -1, alpha -2 and serotonin 2 receptors with Ki values of 324, 2330 and 3510 nM, respectively, whereas it showed only weak activities on D1, D2 and serotonin 1A receptor bindings. Oral administration of TAK-147 (3 mg/kg) significantly accelerated the turnover rates of dopamine, noradrenaline and serotonin in the rat brain. These results suggest that TAK-147 activates the central cholinergic system by specific inhibition of AChE activity without affecting peripheral butyrylcholinesterase activity, and that TAK-147 also moderately activates the monoaminergic systems.
