title: Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7.
abstract: Metabotropic glutamate receptor 7 (mGlu7) is a member of the group III mGlu receptors (mGlus), encompassed by mGlu4, mGlu6, mGlu7, and mGlu8. mGlu7 is highly expressed in the presynaptic active zones of both excitatory and inhibitory synapses, and activation of the receptor regulates the release of both glutamate and GABA. mGlu7 is thought to be a relevant therapeutic target for a number of neurological and psychiatric disorders, and polymorphisms in the GRM7 gene have been linked to autism, depression, ADHD, and schizophrenia. Here we report two new pan-group III mGlu positive allosteric modulators, VU0155094 and VU0422288, which show differential activity at the various group III mGlus. Additionally, both compounds show probe dependence when assessed in the presence of distinct orthosteric agonists. By pairing studies of these nonselective compounds with a synapse in the hippocampus that expresses only mGlu7, we have validated activity of these compounds in a native tissue setting. These studies provide proof-of-concept evidence that mGlu7 activity can be modulated by positive allosteric modulation, paving the way for future therapeutics development.
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, ‡Department of Pharmacology and Vanderbilt Institute of Chemical Biology, and §Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37212, United States.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Jalan-Sakrikar
authors.forename: Julie R
authors.initials: JR
authors.lastname: Field
authors.forename: Rebecca
authors.initials: R
authors.lastname: Klar
authors.forename: Margrith E
authors.initials: ME
authors.lastname: Mattmann
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Gregory
authors.forename: Rocio
authors.initials: R
authors.lastname: Zamorano
authors.forename: Darren W
authors.initials: DW
authors.lastname: Engers
authors.forename: Sean R
authors.initials: SR
authors.lastname: Bollinger
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.forename: Emily L
authors.initials: EL
authors.lastname: Days
authors.forename: L Michelle
authors.initials: LM
authors.lastname: Lewis
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Utley
authors.forename: Miguel
authors.initials: M
authors.lastname: Hurtado
authors.forename: Delphine
authors.initials: D
authors.lastname: Rigault
authors.forename: Francine
authors.initials: F
authors.lastname: Acher
authors.forename: Adam G
authors.initials: AG
authors.lastname: Walker
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Melancon
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Zixiu
authors.initials: Z
authors.lastname: Xiang
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
mesh_terms: D000083:Acetanilides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D018683:Excitatory Amino Acid Agents / Q000737:chemistry* / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008810:Mice, Inbred C57BL; D010848:Picolinic Acids / Q000737:chemistry / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013793:Thallium / Q000378:metabolism; D014162:Transfection
chemical_list: C114785:2-amino-4-phosphono-propinate; C110733:3,4-dicarboxyphenylglycine; D000083:Acetanilides; D001565:Benzoates; D018683:Excitatory Amino Acid Agents; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D010848:Picolinic Acids; D011422:Propionates; D011758:Pyrroles; D018094:Receptors, Metabotropic Glutamate; C000600510:VU0155094; C000600511:VU0422288; C102719:metabotropic glutamate receptor 7; D018698:Glutamic Acid; D013793:Thallium; D002118:Calcium; D005998:Glycine
keywords: Allosteric modulator; electrophysiology; hippocampus; metabotropic glutamate receptor