Discovery of the First Highly M5-Preferring Muscarinic Acetylcholine Receptor Ligand, an M5 Positive Allosteric Modulator Derived from a Series of 5-Trifluoromethoxy N-Benzyl Isatins

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• 作者：Thomas M. Bridges ; Joy E. Marlo ; Colleen M. Niswender ; Carrie K. Jones ; Satyawan B. Jadhav ; Patrick R. Gentry ; Hyekyung C. Plumley ; C. David Weaver ; P. Jeffrey Conn ; Craig W. Lindsley
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：June 11, 2009
• 年：2009
• 卷：52
• 期：11
• 页码：3445-3448
• 全文大小：137K
• 年卷期：v.52,no.11(June 11, 2009)
• ISSN：1520-4804

文摘

This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca²⁺ mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC₅₀ of approximately 1.16 μM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.