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Research ArticleNeuropharmacology

VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy

Hilary Highfield Nickols, Joannes P. Yuh, Karen J. Gregory, Ryan D. Morrison, Brittney S. Bates, Shaun R. Stauffer, Kyle A. Emmitte, Michael Bubser, Weimin Peng, Michael T. Nedelcovych, Analisa Thompson, Xiaohui Lv, Zixiu Xiang, J. Scott Daniels, Colleen M. Niswender, Craig W. Lindsley, Carrie K. Jones and P. Jeffrey Conn
Journal of Pharmacology and Experimental Therapeutics January 2016, 356 (1) 123-136; DOI: https://doi.org/10.1124/jpet.115.226597
Hilary Highfield Nickols
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Joannes P. Yuh
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Karen J. Gregory
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Ryan D. Morrison
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Brittney S. Bates
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Shaun R. Stauffer
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Kyle A. Emmitte
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Michael Bubser
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Weimin Peng
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Michael T. Nedelcovych
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Analisa Thompson
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Xiaohui Lv
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Zixiu Xiang
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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J. Scott Daniels
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Colleen M. Niswender
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Craig W. Lindsley
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Carrie K. Jones
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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P. Jeffrey Conn
Department of Pathology, Microbiology and Immunology, Division of Neuropathology (H.H.N., J.P.Y.), Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery (H.H.N., R.D.M., B.S.B., K.A.E., M.B., W.P., M.T.N., A.T., X.L., Z.X., J.S.D., C.M.N., C.W.L., C.K.J., P.J.C.), Department of Chemistry and Vanderbilt Institute of Chemical Biology (S.R.S., K.A.E., C.W.L.) Vanderbilt University Medical Center, Nashville, Tennessee; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.)
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Abstract

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) have potential applications in the treatment of fragile X syndrome, levodopa-induced dyskinesia in Parkinson disease, Alzheimer disease, addiction, and anxiety; however, clinical and preclinical studies raise concerns that complete blockade of mGlu5 and inverse agonist activity of current mGlu5 NAMs contribute to adverse effects that limit the therapeutic use of these compounds. We report the discovery and characterization of a novel mGlu5 NAM, N,N-diethyl-5-((3-fluorophenyl)ethynyl)picolinamide (VU0477573) that binds to the same allosteric site as the prototypical mGlu5 NAM MPEP but displays weak negative cooperativity. Because of this weak cooperativity, VU0477573 acts as a “partial NAM” so that full occupancy of the MPEP site does not completely inhibit maximal effects of mGlu5 agonists on intracellular calcium mobilization, inositol phosphate (IP) accumulation, or inhibition of synaptic transmission at the hippocampal Schaffer collateral-CA1 synapse. Unlike previous mGlu5 NAMs, VU0477573 displays no inverse agonist activity assessed using measures of effects on basal [3H]inositol phosphate (IP) accumulation. VU0477573 acts as a full NAM when measuring effects on mGlu5-mediated extracellular signal-related kinases 1/2 phosphorylation, which may indicate functional bias. VU0477573 exhibits an excellent pharmacokinetic profile and good brain penetration in rodents and provides dose-dependent full mGlu5 occupancy in the central nervous system (CNS) with systemic administration. Interestingly, VU0477573 shows robust efficacy, comparable to the mGlu5 NAM MTEP, in models of anxiolytic activity at doses that provide full CNS occupancy of mGlu5 and demonstrate an excellent CNS occupancy-efficacy relationship. VU0477573 provides an exciting new tool to investigate the efficacy of partial NAMs in animal models.

Footnotes

    • Received June 5, 2015.
    • Accepted October 23, 2015.
  • Funding for this research was provided by the National Institutes of Health [Grants R01MH062646, R37NS031373, U19MH097056, R01DA023947]. H.H.N. is supported by startup funds from the Vanderbilt Department of Pathology, Microbiology, and Immunology. K.J.G. is supported by a National Health and Medical Research Council (Australia) C. J. Martin postdoctoral training fellowship. All animal studies were performed using Institutional Animal Care and Use Committee–approved protocols.

  • dx.doi.org/10.1124/jpet/115/226597.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 356 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 356, Issue 1
1 Jan 2016
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Research ArticleNeuropharmacology

VU0477573: Partial Negative Allosteric Modulator of mGlu5

Hilary Highfield Nickols, Joannes P. Yuh, Karen J. Gregory, Ryan D. Morrison, Brittney S. Bates, Shaun R. Stauffer, Kyle A. Emmitte, Michael Bubser, Weimin Peng, Michael T. Nedelcovych, Analisa Thompson, Xiaohui Lv, Zixiu Xiang, J. Scott Daniels, Colleen M. Niswender, Craig W. Lindsley, Carrie K. Jones and P. Jeffrey Conn
Journal of Pharmacology and Experimental Therapeutics January 1, 2016, 356 (1) 123-136; DOI: https://doi.org/10.1124/jpet.115.226597

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Research ArticleNeuropharmacology

VU0477573: Partial Negative Allosteric Modulator of mGlu5

Hilary Highfield Nickols, Joannes P. Yuh, Karen J. Gregory, Ryan D. Morrison, Brittney S. Bates, Shaun R. Stauffer, Kyle A. Emmitte, Michael Bubser, Weimin Peng, Michael T. Nedelcovych, Analisa Thompson, Xiaohui Lv, Zixiu Xiang, J. Scott Daniels, Colleen M. Niswender, Craig W. Lindsley, Carrie K. Jones and P. Jeffrey Conn
Journal of Pharmacology and Experimental Therapeutics January 1, 2016, 356 (1) 123-136; DOI: https://doi.org/10.1124/jpet.115.226597
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