Design, synthesis and structure-activity relationship of N-substituted tropane muscarinic acetylcholine receptor antagonists

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• 作者：Dramane I. Lainé ; ^&dagger ; ; Hongxing Yan ; Haibo Xie ; Roderick S. Davis ; Jeremy Dufour ; Katherine L. Widdowson ; Michael R. Palovich ; Zehong Wan ; James J. Foley ; Dulcie B. Schmidt ; Gerald E. Hunsberger ; Miriam Burman ; Alicia M. Bacon ; Edward F. Webb ; Mark A. Luttmann ; Michael Salmon^&Dagger ; ; Henry M. Sarau ; Sandra T. Umbrecht ; Philip S. Landis ; Brian J. Peck ; Jakob Busch-Petersen ; ^{jakob.2.busch-petersen@gsk.com}
• 关键词：Inhaled ; Muscarinic antagonist ; COPD ; Tropane ; Quaternary ammonium salts
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 May, 2012
• 卷：22
• 期：9
• 页码：3366-3369
• 文件大小：378 K

摘要

A novel series of N-substituted tropane derivatives was characterized as potent muscarinic acetylcholine receptor antagonists (mAChRs). Kinetic washout studies showed that the N-endosubstituted analog 24 displayed much slower reversibility at mAChRs than the methyl-substituted parent molecule darotropium. In addition, it was shown that this characteristic appeared to translate into enhanced which duration of action in a mouse model of bronchonstriction.