title: Optimization of the choline transporter (CHT) inhibitor ML352: Development of VU6001221, an improved in vivo tool compound.
abstract: This Letter describes the further lead optimization of the CHT inhibitor probe, ML352 (VU0476201), and the development of VU6001221, an improved in vivo tool. A multi-dimensional optimization effort encountered steep SAR, and ultimately, subtle tuning of the electronics of the central phenyl core provided VU6001221, a CHT inhibitor with comparable potency for choline uptake inhibition as ML352, yet improved PK and CNS penetration. Moreover, VU6001221 enabled evaluation, for the first time, of a CHT inhibitor in a standard preclinical rodent cognition model, novel object recognition (NOR). We observed VU6001221 to elicit a dose-responsive increase in NOR, raising the possibility of agonism of synaptic α7 nicotinic ACh receptors by elevated extracellular choline, that if confirmed would represent a novel molecular strategy to enhance cognition.
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Jeanette L
authors: JL
authors: Bertron
authors: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Elizabeth A
authors: EA
authors: Ennis
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Christopher J
authors: CJ
authors: Tarr
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Jane
authors: J
authors: Wright
authors: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Jonathan W
authors: JW
authors: Dickerson
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Charles W
authors: CW
authors: Locuson
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Anna L
authors: AL
authors: Blobaum
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Jerri M
authors: JM
authors: Rook
authors: FAU Brain Institute, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL 33458, USA. Electronic address: rblakely@fau.edu.
authors: Randy D
authors: RD
authors: Blakely
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.
authors: Craig W
authors: CW
authors: Lindsley
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000187:drug effects*; D010080:Oxazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D007555:Isoxazoles; D026901:Membrane Transport Proteins; C000603315:N-((3-isopropylisoxazol-5-yl)methyl)-4-methoxy-3-((1-methylpiperidin-4-yl)oxy)benzamide; D010080:Oxazoles; D010880:Piperidines; C000621781:VU6001221; C065637:choline transporter
keywords: Choline transporter (CHT); Cognition; ML352; Novel object recognition (NOR); Structure–Activity Relationship (SAR)