title: Discovery of ML326: The first sub-micromolar, selective M5 PAM.
abstract: This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409nM and 500nM, respectively) with excellent mAChR selectivity (M1-M4 EC50s >30μM) and a robust 20-fold leftward shift of the ACh CRC.
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Gentry
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.forename: Atin
authors.initials: A
authors.lastname: Lamsal
authors.forename: Paige N
authors.initials: PN
authors.lastname: Vinson
authors.forename: Emery
authors.initials: E
authors.lastname: Smith
authors.forename: Peter
authors.initials: P
authors.lastname: Chase
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hodder
authors.forename: Julie L
authors.initials: JL
authors.lastname: Engers
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
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: D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; C584276:ML326; D011976:Receptors, Muscarinic
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