title: Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site interaction crossover.
abstract: We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topologically similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Manka
authors.forename: Paige N
authors.initials: PN
authors.lastname: Vinson
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Gregory
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhou
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: Kiran
authors.initials: K
authors.lastname: Gogi
authors.forename: Emily
authors.initials: E
authors.lastname: Days
authors.forename: Satya
authors.initials: S
authors.lastname: Jadhav
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Herman
authors.forename: Hilde
authors.initials: H
authors.lastname: Lavreysen
authors.forename: Claire
authors.initials: C
authors.lastname: Mackie
authors.forename: José M
authors.initials: JM
authors.lastname: Bartolomé
authors.forename: Gregor J
authors.initials: GJ
authors.lastname: Macdonald
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000495:Allosteric Site / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D004987:Ethers / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D009536:Niacinamide / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011618:Psychotic Disorders / Q000188:drug therapy; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D004987:Ethers; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D009536:Niacinamide