Evidence map›Paper›PMID 26503377›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2016

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 and 8 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of pharmacology and experimental therapeutics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.

0numbers the graph read from it
0cells of the map it votes in
14citing papers in PubMed
2.7field-weighted citation impact, top 10% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

14 citing papers in PubMed, 35 citations in OpenAlex.

  1. Review
  2. Review
  3. Review
  4. Review
  5. Review
  6. Article
  7. Article
  8. Article
  9. Frontiers in pharmacology · 2018
    Article
  10. Article
  11. Review
  12. Review
  13. Article
  14. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 3 institutions in 2 countries.

Hilary Highfield NickolsDepartment 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.) hilary.nickols@vanderbilt.edu.
Joannes P YuhDepartment 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.).
Karen J GregoryDepartment 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.).
Ryan D MorrisonDepartment 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.).
Brittney S BatesDepartment 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.).
Shaun R StaufferDepartment 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.).
Kyle A EmmitteDepartment 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.).
Michael BubserDepartment 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.).
Weimin PengDepartment 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.).
Michael T NedelcovychDepartment 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.).
Analisa ThompsonDepartment 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.).
Xiaohui LvDepartment 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.).
Zixiu XiangDepartment 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.).
J Scott DanielsDepartment 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.).
Colleen M NiswenderDepartment 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.).
Craig W LindsleyDepartment 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.).
Carrie K JonesDepartment 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.).
P Jeffrey ConnDepartment 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.).
Anna Needs Neuroblastoma Answers · USMonash University · AUVanderbilt University Medical Center · US

Funding

TRAINING IN PHARMACOLOGICAL SCIENCEST32GM007628 · NIGMS · VANDERBILT UNIVERSITY · PI BARNETT, JOEY VICTOR, KAVALALI, EGE T · 1985 to 2022
$11.2M
REGULATION OF SIGNALING BY MGLUR5R01MH062646 · NIMH · VANDERBILT UNIVERSITY · PI P Jeffrey Conn, COLLEEN M NISWENDER · 2001 to 2026
$10.9M
Research Project: Sensory and Multisensory Contributions to AutismU54HD083211 · NICHD · VANDERBILT UNIVERSITY MEDICAL CENTER · PI DYKENS, ELISABETH MAY · 2015 to 2019
$7.1M
Lead Optimization & Development of Back-Up mGlu5 NAM Candidates for Treatment ofU19MH097056 · NIMH · VANDERBILT UNIVERSITY · PI CONN, P JEFFREY · 2013 to 2015
$3.8M
Functions of Metabotropic Glutamate Receptor SubtypesR37NS031373 · NINDS · VANDERBILT UNIVERSITY · PI CONN, P JEFFREY · 2014 to 2020
$3.5M
Partial Antagonists of mGluR5 for Treatment of Cocaine AddictionR01DA023947 · NIDA · VANDERBILT UNIVERSITY · PI LINDSLEY, CRAIG · 2008 to 2012
$2.1M
Postdoctoral Training in CNS Drug Discovery ResearchT32MH093366 · NIMH · VANDERBILT UNIVERSITY · PI CONN, P JEFFREY · 2011 to 2015
$1.0M
NICHD NIH HHS U54 HD083211NIDA NIH HHS R01 DA023947NIDA NIH HHS R01DA023947NIGMS NIH HHS T32 GM007628NIMH NIH HHS R01 MH062646NIMH NIH HHS R01MH062646NIMH NIH HHS T32 MH093366NIMH NIH HHS U19 MH097056NIMH NIH HHS U19MH097056NINDS NIH HHS R37 NS031373NINDS NIH HHS R37NS031373
6 · The paper itself

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 [(3)H]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.

Indexed as

Allosteric RegulationAnimalsAnti-Anxiety AgentsAstrocytesBehavior, AnimalBrainDose-Response Relationship, DrugDrug DiscoveryGABA AgonistsHEK293 CellsHumansInositol PhosphatesMAP Kinase Signaling SystemMembrane PotentialsMiceMice, Inbred C57BL6-methyl-2-(phenylethynyl)pyridineAnti-Anxiety AgentsGABA AgonistsInositol PhosphatesN,N-diethyl-5-((3-fluorophenyl)ethynyl)picolinamidePicolinic AcidsPyridinesReceptor, Metabotropic Glutamate 5

Identifiers

PMID26503377
PMCPMC4702078
OpenAlexW1856877948

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.