Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu₃) NAM probe (ML289) derived from a closely related mGlu₅ PAM

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• 作者：Douglas J. Sheffler^a ; ^b ; ^c ; ^&dagger ; ; Cody J. Wenthur^a ; ^b ; ^&dagger ; ; Joshua A. Bruner^b ; ^&dagger ; ; Sheridan J.S. Carrington^a ; ^b ; Paige N. Vinson^a ; ^b ; Kiran K. Gogi^a ; ^b ; Anna L. Blobaum^a ; ^b ; ^c ; Ryan D. Morrison^a ; ^b ; ^c ; Mitchell Vamos^e ; Nicholas D.P. Cosford^e ; Shaun R. Stauffer^a ; ^b ; ^d ; J. Scott Daniels^a ; ^b ; ^c ; Colleen M. Niswender^a ; ^b ; P. Jeffrey Conn^a ; ^b ; ^c ; Craig W. Lindsley^a ; ^b ; ^c ; ^d ; ^{craig.lindsley@vanderbilt.edu}
• 关键词：Metabotropic glutamate receptor 3 ; mGlu3 ; Molecular switch ; NAM
• 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 June, 2012
• 卷：22
• 期：12
• 页码：3921-3925
• 文件大小：1613 K

摘要

Herein we report the discovery and SAR of a novel metabotropic glutamate receptor 3 (mGlu₃) NAM probe (ML289) with 15-fold selectivity versus mGlu₂. The mGlu₃ NAM was discovered via a 鈥榤olecular switch鈥?from a closely related, potent mGlu₅ positive allosteric modulator (PAM), VU0092273. This NAM (VU0463597, ML289) displays an IC₅₀ value of 0.66 渭M and is inactive against mGlu₅.