Targeting selective activation of M(1) for the treatment of Alzheimer's disease: further chemical optimization and pharmacological characterization of the M(1) positive allosteric modulator ML169

ACS Chem Neurosci. 2012 Nov 21;3(11):884-95. doi: 10.1021/cn300068s. Epub 2012 Jul 18.


The M(1) muscarinic acetylcholine receptor is thought to play an important role in memory and cognition, making it a potential target for the treatment of Alzheimer's disease (AD) and schizophrenia. Moreover, M(1) interacts with BACE1 and regulates its proteosomal degradation, suggesting selective M(1) 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 M(1) 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 EC(50) of 310 nM. The new compounds maintained complete selectivity for the M(1) receptor over the other subtypes (M(2)-M(5)), 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 M(1) PAMs may afford a disease-modifying role in the treatment of AD.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation / drug effects*
  • Alzheimer Disease / drug therapy*
  • Animals
  • Cognition / drug effects
  • Drug Discovery
  • Indoles / chemical synthesis
  • Indoles / pharmacology*
  • Muscarinic Agonists / chemical synthesis
  • Muscarinic Agonists / pharmacology*
  • Myotonin-Protein Kinase
  • Neurons / drug effects
  • Protein Serine-Threonine Kinases / drug effects
  • Rats
  • Receptor, Muscarinic M1 / drug effects*
  • Receptor, Muscarinic M1 / genetics
  • Sulfones / chemical synthesis
  • Sulfones / pharmacology*


  • Indoles
  • Muscarinic Agonists
  • Receptor, Muscarinic M1
  • Sulfones
  • VU 0405652
  • Myotonin-Protein Kinase
  • Protein Serine-Threonine Kinases