Abstract
Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenylethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phencyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders.
Footnotes
↵
The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants 1F32-NS049865, R01-NS031373]; the National Institutes of Health National Institute of Mental Health [Grants R01-MH062646, R01-MH074953]; and the National Institutes of Health National Institute on Drug Abuse [Grant 1R01-DA023947-01]. Vanderbilt is a center in the National Institutes of Health-supported Molecular Libraries Screening Centers Network.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.067207.
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ABBREVIATIONS:
- CNS
- central nervous system
- mGluR
- metabotropic glutamate receptor
- PAM
- positive allosteric modulator
- ESI
- electrospray ionization
- NAM
- negative allosteric modulator
- MS
- mass spectrometry
- MS/MS
- tandem mass spectrometry
- MPEP
- 2-methyl-6-(phenylethynyl)pyridine hydrochloride
- NMDA
- N-methyl-d-aspartate
- DHPG
- dihydroxyphenylglycine
- SAR
- structure-activity relationship
- methoxyPEPy
- 3-methoxy-5-(pyridin-2-ylethynyl)pyridine
- CDPPB
- 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide
- HRMS
- high-resolution mass spectrometry
- CPPHA
- N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide
- 5MPEP
- 5-methyl-6-(phenylethynyl)pyridine
- HPLC
- high-performance liquid chromatography
- HEK
- human embryonic kidney
- DMEM
- Dulbecco's modified Eagle's medium
- PK
- pharmacokinetic
- PCP
- phencyclidine
- DMSO
- dimethyl sulfoxide
- FDSS
- functional drug screening system
- M1
- muscarinic receptor subtype 1
- Veh
- vehicle
- VI
- variable interval
- FBS
- fetal bovine serum
- CRC
- concentration-response curve
- MTEP
- 3-((2-methyl-4-thiazolyl)ethynyl)pyridine
- HTS
- high-throughput screening
- BCD
- β-cyclodextrin
- ADX-47273
- S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone
- VU0366025
- (3-hydroxyazetidin-1-yl)(4-phenylehtynyl)phenyl)methanone
- VU0366028
- (4-((3,4-difluorophenyl)ethynyl)phenyl) (morpholino)methanone
- VU0366029
- (3-hydroxyazetidin-1-yl)(4-(3-fluorophenyl)ethynyl)phenyl)methanone
- VU0366024
- (4-methanolpiperidin-1-yl)(4-phenylethynyl)phenyl)methanone
- VU0366027
- (4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxymethyl)piperidin-1-yl)methanone
- VU0366030
- (4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone
- VU0040228
- 5-(3,5-dimethoxyphenyl)-3-(pyridine-2-yl)-1,2,4-oxadiazole
- VU0285683
- 3-fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile
- VU0255037
- 5-(3-bromophenyl)-3-(pyridine-2-yl)-1,2,4-oxadiazole
- VU0067144
- 5-(3-chlorophenyl)-3-(pyridine-2-yl)-1,2,4-oxadiazole
- VU0255038
- 3-(pyridine-2-yl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole
- VU0092273
- (4-hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone
- VU0240381
- (4-morphonyl)(4-phenylethynyl)phenyl) methanone
- VU0366026
- (4-hydroxypiperidin-1-yl)(4-(3-fluorophenyl)ethynyl)phenyl)methanone
- VU0366031
- (4-morphonyl)(4-(3-fluorophenyl) ethynyl)phenyl)methanone
- VU0360175
- (6-((3-fluorophenyl)ethynyl)pyridin-3-yl)(morpholino)methanone
- VU0361747
- (6-((3-fluorophenyl)ethynyl)pyridin-3-yl)(4-hydroxypiperidin-1-yl)methanone
- VU0360172
- N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide
- VU0029251
- 2-(methylthio)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-amine
- VU0028316
- (E)-3-(3-(2-methyl-5-phenylfuran-3-carboxamido)phenyl)acrylic acid.
- Received July 9, 2010.
- Accepted October 4, 2010.
- U.S. Government work not protected by U.S. copyright
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Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity
