title: The effect of mGlu5 receptor positive allosteric modulators on signaling molecules in brain slices.
abstract: Positive allosteric modulators of metabotropic glutamate receptor subtype 5 (mGlu5) have promising therapeutic potential. The effects of selective mGlu5 receptor positive allosteric modulators on signaling molecules in brain slices have not been previously reported. The current study demonstrated that the selective mGlu5 receptor positive allosteric modulator, N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2yl)-methyl]phenyl}-2-hydrobenzamide (CPPHA) potentiated the response to a subthreshold concentration of 3,5-dihydroxy-phenylglycine (DHPG) on extracellular signal-regulated protein kinase (ERK) and cyclic-AMP responsive element-binding protein (CREB) activity, as well as N-methyl d-aspartate (NMDA) receptor subunit NR1 phosphorylation in cortical and hippocampal slices. These results suggest that allosteric modulators of mGlu5 receptor could have physiologically significant effects by potentiating the actions of glutamate.
authors.affiliation: Wyeth Neuroscience Discovery Research, CN 8000, Princeton, NJ 08543, USA. liuf2@wyeth.com
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Guoming
authors.initials: G
authors.lastname: Zhang
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Hornby
authors.forename: Dmytro
authors.initials: D
authors.lastname: Vasylyev
authors.forename: Mark
authors.initials: M
authors.lastname: Bowlby
authors.forename: Kaapjoo
authors.initials: K
authors.lastname: Park
authors.forename: Adam
authors.initials: A
authors.lastname: Gilbert
authors.forename: Karen
authors.initials: K
authors.lastname: Marquis
authors.forename: Terrance H
authors.initials: TH
authors.lastname: Andree
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D010797:Phthalimides / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001549:Benzamides; D017362:Cyclic AMP Response Element-Binding Protein; D018691:Excitatory Amino Acid Antagonists; C481448:N-(4-chloro-2-((1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl)phenyl)-2-hydroxybenzamide; C409466:NR1 NMDA receptor; D010797:Phthalimides; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D012118:Resorcinols; C079215:3,5-dihydroxyphenylglycine; D048049:Extracellular Signal-Regulated MAP Kinases; D005998:Glycine