Selective Muscarinic Antagonists. I. Synthesis and Antimuscarinic Properties of 4-Piperidyl Benzhydrylcarbamate Derivatives

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概要

• 論文の詳細を見る

• A series of 1-substituetd-4-piperidyl benzhydrylcarbamate derivatives were synthesized and evaluated for binding affinity to M_1,M_2 and M_3 receptors, and for antimuscarinic activities. Receptor binding assays indicated that 1-benzyl-4-piperidyl benzhydrylcarbamate derivatives showed higher affinities for M_1 and M_3 receptors, and good selectivities for M_3 over M_2 receptor, than the corresponding ester analog. These results indicate that the urethane bond is a novel linker for muscarinic antagonists, and serves to lock the molecular conformation and allows the hydrophobic portion and cationic site of the molecule to bind to M_1 and M_3 muscarinic receptors. Among the prepared compounds, 1-(4-methylaminobenzyl)-4-piperidyl benzhydrylcarbamate monohydrochloride (18b, YM-58790) exhibited potent inhibitory activity on bladder pressure in reflexly-evoked rhythmic contraction, comparable to oxybutynin and was approximately ten times less inhibitory on oxotremorine-induced salivary secretion than oxybutynin in rats. Further evaluation of antimuscarinic effects on bradycardia and pressor in pithed rats, and on tremor in mice, demonstrate that YM-58790 can be useful for treatment of urinary urge incontinence as a bladder-selective M_3 antagonist with fewer side effects.

• 公益社団法人日本薬学会の論文
• 1998-08-15

著者

• 池田 潔

  School Of Pharmaceutical Sciences University Of Shizuoka

• 池田 潔

  Tanabe Seiyaku Co. Ltd. Saitama Jpn

• Takeuchi M

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Takeuchi Makoto

  Chemistry Research Laboratories Astellas Pharmaceutical Inc.

• MORIHIRA Koichiro

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,

• TAKEUCHI Makoto

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,

• SHIBANUMA Tadao

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,

• ISOMURA Yasuo

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,

• Takeuchi M

  Chemistry Research Laboratories Astellas Pharmaceutical Inc.

• Isomura Y

  Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn

• Ikeda Kiyoshi

  Department Of Biochemistry Osaka University Of Pharmaceutical Sciences

• Hayakawa Miho

  R & D Division Daiichi Sankyo Co. Ltd.

• NAITO Ryo

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,

• IKEDA Ken

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,

• Shibanuma Tadao

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Shibanuma Tadao

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.

• Naito R

  Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn

• Naito Ryo

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• HAYAKAWA Masahiko

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,

• 池田 かおり

  Developmental Research Laboratories Shionogi & Co. Ltd.

• Ikeda Kaori

  Developmental Research Laboratories Shionogi & Co. Ltd.

• Morihira K

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

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