title: Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM.
abstract: Herein we report the discovery and SAR of a novel metabotropic glutamate receptor 3 (mGlu(3)) NAM probe (ML289) with 15-fold selectivity versus mGlu(2). The mGlu(3) NAM was discovered via a 'molecular switch' from a closely related, potent mGlu(5) positive allosteric modulator (PAM), VU0092273. This NAM (VU0463597, ML289) displays an IC(50) value of 0.66 μM and is inactive against mGlu(5).
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Sheffler
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Wenthur
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bruner
authors.forename: Sheridan J S
authors.initials: SJ
authors.lastname: Carrington
authors.forename: Paige N
authors.initials: PN
authors.lastname: Vinson
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Gogi
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morrison
authors.forename: Mitchell
authors.initials: M
authors.lastname: Vamos
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000494:Allosteric Regulation; D002460:Cell Line; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D055808:Drug Discovery; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000494:pharmacology; D010539:Permeability; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
chemical_list: C575095:ML289; D015335:Molecular Probes; D010880:Piperidines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C575096:VU0092273; C102718:metabotropic glutamate receptor 3; D018698:Glutamic Acid