VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy.
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.
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.) hilary.nickols@vanderbilt.edu.
Hilary Highfield
HH
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.).
Joannes P
JP
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.).
Karen J
KJ
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.).
Ryan D
RD
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.).
Brittney S
BS
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.).
Shaun R
SR
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.).
Kyle A
KA
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.).
Michael
M
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.).
Weimin
W
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.).
Michael T
MT
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.).
Analisa
A
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.).
Xiaohui
X
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.).
Zixiu
Z
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.).
J Scott
JS
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.).
Colleen M
CM
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.).
Craig W
CW
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.).
Carrie K
CK
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.).
P Jeffrey
PJ
Conn
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D018755:GABA Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010848:Picolinic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D014151:Anti-Anxiety Agents; D018755:GABA Agonists; D007295:Inositol Phosphates; C000605813:N,N-diethyl-5-((3-fluorophenyl)ethynyl)picolinamide; D010848:Picolinic Acids; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; C121465:6-methyl-2-(phenylethynyl)pyridine