title: Design of 4-Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2.
abstract: Both orthosteric and allosteric antagonists of the group II metabotropic glutamate receptors (mGlus) have been used to establish a link between mGlu2/3 inhibition and a variety of CNS diseases and disorders. Though these tools typically have good selectivity for mGlu2/3 versus the remaining six members of the mGlu family, compounds that are selective for only one of the individual group II mGlus have proved elusive. Herein we report on the discovery of a potent and highly selective mGlu2 negative allosteric modulator 58 (VU6001192) from a series of 4-oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides. The concept for the design of this series centered on morphing a quinoline series recently disclosed in the patent literature into a chemotype previously used for the preparation of muscarinic acetylcholine receptor subtype 1 positive allosteric modulators. Compound 58 exhibits a favorable profile and will be a useful tool for understanding the biological implications of selective inhibition of mGlu2 in the CNS.
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Felts
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Alice L
authors.initials: AL
authors.lastname: Rodriguez
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Katrina A
authors.initials: KA
authors.lastname: Smith
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Engers
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morrison
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Frank W
authors.initials: FW
authors.lastname: Byers
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Locuson
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Sichen
authors.initials: S
authors.lastname: Chang
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Daryl F
authors.initials: DF
authors.lastname: Venable
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Emmitte
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects; D055808:Drug Discovery; D051379:Mice; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D011804:Quinolines; D015363:Quinolones; D043643:Receptor, Muscarinic M1; D018094:Receptors, Metabotropic Glutamate; C000605771:VU6001192; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3