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VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy.
Nickols, Hilary Highfield; Yuh, Joannes P; Gregory, Karen J; Morrison, Ryan D; Bates, Brittney S; Stauffer, Shaun R; Emmitte, Kyle A; Bubser, Michael; Peng, Weimin; Nedelcovych, Michael T; Thompson, Analisa; Lv, Xiaohui; Xiang, Zixiu; Daniels, J Scott; Niswender, Colleen M; Lindsley, Craig W; Jones, Carrie K; Conn, P Jeffrey.
Afiliación
  • Nickols HH; 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.), Departme
  • Yuh JP; 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.), Departme
  • Gregory KJ; 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.), Departme
  • Morrison RD; 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.), Departme
  • Bates BS; 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.), Departme
  • Stauffer SR; 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.), Departme
  • Emmitte KA; 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.), Departme
  • Bubser M; 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.), Departme
  • Peng W; 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.), Departme
  • Nedelcovych MT; 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.), Departme
  • Thompson A; 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.), Departme
  • Lv X; 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.), Departme
  • Xiang Z; 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.), Departme
  • Daniels JS; 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.), Departme
  • Niswender CM; 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.), Departme
  • Lindsley CW; 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.), Departme
  • Jones CK; 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.), Departme
  • Conn PJ; 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.), Departme
J Pharmacol Exp Ther ; 356(1): 123-36, 2016 Jan.
Article en En | MEDLINE | ID: mdl-26503377
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Ácidos Picolínicos / Agonistas del GABA / Receptor del Glutamato Metabotropico 5 Límite: Animals / Humans Idioma: En Revista: J Pharmacol Exp Ther Año: 2016 Tipo del documento: Article
Texto completo
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Ácidos Picolínicos / Agonistas del GABA / Receptor del Glutamato Metabotropico 5 Límite: Animals / Humans Idioma: En Revista: J Pharmacol Exp Ther Año: 2016 Tipo del documento: Article