title: Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold.
abstract: This Letter describes the hit-to-lead progression and SAR of a series of biphenyl acetylene compounds derived from an HTS screening campaign targeting the mGlu(5) receptor. 'Molecular switches' were identified that modulated modes of pharmacology, and several compounds within this series were shown to be efficacious in reversal of amphetamine induced hyperlocomotion in rats after ip dosing, a preclinical model that shows similar positive effects with known antipsychotic agents.
authors.affiliation: Department of Pharmacology, Vanderbilt Medical Center, Nashville, TN 37232, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: Jason T
authors.initials: JT
authors.lastname: Manka
authors.forename: Alice L
authors.initials: AL
authors.lastname: Rodriguez
authors.forename: Paige N
authors.initials: PN
authors.lastname: Vinson
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
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; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D001643:Bridged Bicyclo Compounds; D007769:Lactams; D018094:Receptors, Metabotropic Glutamate