Targeting Selective Activation of M1 for the Treatment of Alzheimer鈥檚 Disease: Further Chemical Optimization and Pharmacological Characterization of the M1 Positive Allosteric Mo

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• 作者：James C. Tarr ; Mark L. Turlington ; Paul R. Reid ; Thomas J. Utley ; Douglas J. Sheffler ; Hyekyung P. Cho ; Rebecca Klar ; Tristano Pancani ; Michael T. Klein ; Thomas M. Bridges ; Ryan D. Morrison ; Anna L. Blobaum ; Zixui Xiang ; J. Scott Daniels ; Colleen M. Niswender ; P. Jeffrey Conn ; Michael R. Wood ; Craig W. Lindsley
• 刊名：ACS Chemical Neuroscience
• 出版年：2012
• 出版时间：November 21, 2012
• 年：2012
• 卷：3
• 期：11
• 页码：884-895
• 全文大小：604K
• 年卷期：v.3,no.11(November 21, 2012)
• ISSN：1948-7193

文摘

The M₁ muscarinic acetylcholine receptor is thought to play an important role in memory and cognition, making it a potential target for the treatment of Alzheimer鈥檚 disease (AD) and schizophrenia. Moreover, M₁ interacts with BACE1 and regulates its proteosomal degradation, suggesting selective M₁ activation could afford both palliative cognitive benefit as well as disease modification in AD. A key challenge in targeting the muscarinic acetylcholine receptors is achieving mAChR subtype selectivity. Our lab has previously reported the M₁ selective positive allosteric modulator ML169. Herein we describe our efforts to further optimize this lead compound by preparing analogue libraries and probing novel scaffolds. We were able to identify several analogues that possessed submicromolar potency, with our best example displaying an EC₅₀ of 310 nM. The new compounds maintained complete selectivity for the M₁ receptor over the other subtypes (M₂鈥揗₅), displayed improved DMPK profiles, and potentiated the carbachol (CCh)-induced excitation in striatal MSNs. Selected analogues were able to potentiate CCh-mediated nonamyloidogenic APPs伪 release, further strengthening the concept that M₁ PAMs may afford a disease-modifying role in the treatment of AD.

Keywords:

cs.org/action/doSearch?action=search&searchText=Muscarinic&qsSearchArea=searchText">Muscarinic; cs.org/action/doSearch?action=search&searchText=acetylcholine&qsSearchArea=searchText">acetylcholine; cs.org/action/doSearch?action=search&searchText=positive+allosteric+modulator+%5C%28PAM%5C%29&qsSearchArea=searchText">positive allosteric modulator (PAM); cs.org/action/doSearch?action=search&searchText=ML169&qsSearchArea=searchText">ML169; cs.org/action/doSearch?action=search&searchText=Alzheimer%E2%80%99s+disease+%5C%28AD%5C%29&qsSearchArea=searchText">Alzheimer鈥檚 disease (AD); cs.org/action/doSearch?action=search&searchText=medium+spiny+neurons+%5C%28MSNs%5C%29&qsSearchArea=searchText">medium spiny neurons (MSNs); cs.org/action/doSearch?action=search&searchText=MLPCN&qsSearchArea=searchText">MLPCN