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 Allen 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, P. Jeffrey Conn

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)123-136
Number of pages14
JournalThe Journal of pharmacology and experimental therapeutics
Volume356
Issue number1
DOIs
StatePublished - 1 Jan 2016

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Metabotropic Glutamate 5 Receptor
Central Nervous System
Allosteric Site
Fragile X Syndrome
Inositol Phosphates
N,N-diethyl-5-((3-fluorophenyl)ethynyl)picolinamide
Anti-Anxiety Agents
Dyskinesias
Levodopa
Therapeutic Uses
Synaptic Transmission
Synapses
Parkinson Disease
Rodentia
Hippocampus
Alzheimer Disease
Phosphotransferases
Anxiety
Animal Models
Pharmacokinetics

Cite this

Nickols, Hilary Highfield ; Yuh, Joannes P. ; Gregory, Karen J. ; Morrison, Ryan D. ; Bates, Brittney S. ; Stauffer, Shaun R. ; Emmitte, Kyle Allen ; 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. / VU0477573 : Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy. In: The Journal of pharmacology and experimental therapeutics. 2016 ; Vol. 356, No. 1. pp. 123-136.
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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 [(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.",
author = "Nickols, {Hilary Highfield} and Yuh, {Joannes P.} and Gregory, {Karen J.} and Morrison, {Ryan D.} and Bates, {Brittney S.} and Stauffer, {Shaun R.} and Emmitte, {Kyle Allen} and Michael Bubser and Weimin Peng and Nedelcovych, {Michael T.} and Analisa Thompson and Xiaohui Lv and Zixiu Xiang and Daniels, {J. Scott} and Niswender, {Colleen M.} and Lindsley, {Craig W.} and Jones, {Carrie K.} and Conn, {P. Jeffrey}",
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Nickols, HH, Yuh, JP, Gregory, KJ, Morrison, RD, Bates, BS, Stauffer, SR, Emmitte, KA, Bubser, M, Peng, W, Nedelcovych, MT, Thompson, A, Lv, X, Xiang, Z, Daniels, JS, Niswender, CM, Lindsley, CW, Jones, CK & Conn, PJ 2016, 'VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy', The Journal of pharmacology and experimental therapeutics, vol. 356, no. 1, pp. 123-136. https://doi.org/10.1124/jpet.115.226597

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 Allen; 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.

In: The Journal of pharmacology and experimental therapeutics, Vol. 356, No. 1, 01.01.2016, p. 123-136.

Research output: Contribution to journalArticle

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T2 - Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy

AU - Nickols, Hilary Highfield

AU - Yuh, Joannes P.

AU - Gregory, Karen J.

AU - Morrison, Ryan D.

AU - Bates, Brittney S.

AU - Stauffer, Shaun R.

AU - Emmitte, Kyle Allen

AU - Bubser, Michael

AU - Peng, Weimin

AU - Nedelcovych, Michael T.

AU - Thompson, Analisa

AU - Lv, Xiaohui

AU - Xiang, Zixiu

AU - Daniels, J. Scott

AU - Niswender, Colleen M.

AU - Lindsley, Craig W.

AU - Jones, Carrie K.

AU - Conn, P. Jeffrey

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N2 - 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.

AB - 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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