Selective Muscarinic Antagonists. II. Synthesis and Antimuscarinic Properties of Biphenylylcarbamate Derivatives

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概要

• 論文の詳細を見る

• A novel series of biphenylylcarbamate derivaties were synthesized and evaluated for binding to M_1,M_2 and M_3 receptors and for antimuscarinic activities. Receptor binding assays indicated that biphenyl-2-ylcarbamate derivatives had high affinities for M_1 and M_3 receptors and good selectivities for M_3 receptor over M_2 receptor, indicating that the biphenyl-2-yl group is a novel hydrophobic replacement for the benzhydryl group in the muscarinic antagonist field. In this series, quinuclidin-4-yl biphenyl-2-ylcarbamate monohydrochloride (81,YM-46303) exhibited the highest affinities for M_1 and M_3 receptors, and selectivity for M_3 over M_2 receptor. Compared to oxybutynin, YM-46303 showed approximately ten times higher inhibitory activity on bladder pressure in reflexly-evoked rhythimic contration, and about 5-fold greater selectivity for urinary bladder contraction against salivary secretion in rats. Moreover, selective antagonistic activity was also observed in vitro. Further evaluation of antimuscarinic effects on bradycardia and pressor in pithed rats, and on tremor in mice, showed that YM-46303 can be useful for the treatment of urinary urge incontinence as a bladder-selective M_3 antagonist with potent activities and 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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