Targeting selective activation of M1 for the treatment of Alzheimers disease: Further chemical optimization and pharmacological characterization of the M1 positive allosteric modulator ML169

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

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 Alzheimers 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-M5), displayed improved DMPK profiles, and potentiated the carbachol (CCh)-induced excitation in striatal MSNs. Selected analogues were able to potentiate CCh-mediated nonamyloidogenic APPsα release, further strengthening the concept that M1 PAMs may afford a disease-modifying role in the treatment of AD.

Original languageEnglish (US)
Pages (from-to)884-895
Number of pages12
JournalACS Chemical Neuroscience
Volume3
Issue number11
DOIs
StatePublished - Nov 21 2012

Keywords

  • Alzheimers disease (AD)
  • ML169
  • MLPCN
  • Muscarinic
  • acetylcholine
  • medium spiny neurons (MSNs)
  • positive allosteric modulator (PAM)

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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