title: Discovery of VU0431316: a negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety.
abstract: Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of pyrazine analog VU0431316 is described in this Letter. VU0431316 is a potent and selective non-competitive antagonist of mGlu5 that binds at a known allosteric binding site. VU0431316 demonstrates an attractive DMPK profile, including moderate clearance and good bioavailability in rats. Intraperitoneal (IP) dosing of VU0431316 in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists and other anxiolytics, produced dose proportional effects.
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Brittney S
authors: BS
authors: Bates
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Alice L
authors: AL
authors: Rodriguez
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Andrew S
authors: AS
authors: Felts
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Ryan D
authors: RD
authors: Morrison
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Daryl F
authors: DF
authors: Venable
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, 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 Medical Center, Nashville, TN 37232, USA.
authors: Frank W
authors: FW
authors: Byers
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Kera P
authors: KP
authors: Lawson
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: J Scott
authors: JS
authors: Daniels
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Colleen M
authors: CM
authors: Niswender
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Tennessee Valley Healthcare System, U.S. Department of Veterans Affairs, Nashville, TN 37212, USA.
authors: Carrie K
authors: CK
authors: Jones
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: P Jeffrey
authors: PJ
authors: Conn
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors: Craig W
authors: CW
authors: Lindsley
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: kyle.a.emmitte@vanderbilt.edu.
authors: Kyle A
authors: KA
authors: Emmitte
mesh_terms: D000495:Allosteric Site / Q000187:drug effects; D000818:Animals; D001007:Anxiety / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010848:Picolinic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D010848:Picolinic Acids; D011719:Pyrazines; D064529:Receptor, Metabotropic Glutamate 5; C000595739:VU0431316
keywords: Allosteric modulator; Anxiety; CNS; Glutamate; mGlu(5)