title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology, Department of Chemistry, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), and Vanderbilt Institute of Chemical Biology/Chemical Synthesis Core, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
authors.forename: James C
authors.initials: JC
authors.lastname: Tarr
authors.forename: Mark L
authors.initials: ML
authors.lastname: Turlington
authors.forename: Paul R
authors.initials: PR
authors.lastname: Reid
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Utley
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Sheffler
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.forename: Rebecca
authors.initials: R
authors.lastname: Klar
authors.forename: Tristano
authors.initials: T
authors.lastname: Pancani
authors.forename: Michael T
authors.initials: MT
authors.lastname: Klein
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morrison
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.forename: Zixui
authors.initials: Z
authors.lastname: Xiang
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D003071:Cognition / Q000187:drug effects; D055808:Drug Discovery; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D018721:Muscarinic Agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D065636:Myotonin-Protein Kinase; D009474:Neurons / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000187:drug effects* / Q000235:genetics; D013450:Sulfones / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D007211:Indoles; D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; D013450:Sulfones; C560209:VU 0405652; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases