Continued optimization of the MLPCN probe ML071 into highly potent agonists of the hM₁ muscarinic acetylcholine receptor

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• 作者：Bruce J. Melancon^a ; ^c ; ^d ; Rocco D. Gogliotti^a ; ^c ; ^d ; James C. Tarr^a ; ^c ; ^d ; Sam A. Saleh^a ; ^c ; ^d ; Brian A. Chauder^a ; ^c ; ^d ; Evan P. Lebois^a ; ^c ; ^d ; Hyekyung P. Cho^a ; ^c ; ^d ; Thomas J. Utley^a ; ^c ; ^d ; Douglas J. Sheffler^a ; ^c ; Thomas M. Bridges^a ; ^c ; ^d ; Ryan D. Morrison^a ; ^c ; ^d ; J. Scott Daniels^a ; ^c ; ^d ; Colleen M. Niswender^a ; ^c ; ^d ; P. Jeffrey Conn^a ; ^c ; ^d ; Craig W. Lindsley^a ; ^b ; ^c ; ^d ; Michael R. Wood^a ; ^b ; ^c ; ^d ; ^{michael.r.wood@vanderbilt.edu}
• 关键词：Muscarinic acetylcholine receptor 1 ; M1 ; Allosteric ; Agonist ; Bitopic ; ML071 ; VU0364572
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 May, 2012
• 卷：22
• 期：10
• 页码：3467-3472
• 文件大小：2875 K

摘要

This Letter describes the continued optimization of the MLPCN probe molecule ML071. After introducing numerous cyclic constraints and novel substitutions throughout the parent structure, we produced a number of more highly potent agonists of the M₁ mACh receptor. While many novel agonists demonstrated a promising ability to increase soluble APP伪 release, further characterization indicated they may be functioning as bitopic agonists. These results and the implications of a bitopic mode of action are presented.