Neuroprotective activity of the potent and selective mGlula metabotropic glutamate receptor antagonist, (+)-2-methyl-4 carboxyphenylglycine (LY367385): Comparison with LY357366, a broader spectrum antagonist with equal affinity for mGlula and mGlu5 receptors

V. Bruno, G. Battaglia, A. Kingston, M. J. O'Neill, M. V. Catania, R. Di Grezia, F. Nicoletti

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Abstract

(+)-2-Methyl-4-carboxyphenylglycine (LY367385), a potent and selective antagonist of mGlu1a metabotropic glutamate receptors, was neuroprotective in the following in vitro and in vivo models of excitotoxic death: (i) mixed cultures of murine cortical cells transiently exposed to N-methyl-D-aspartate (NMDA); (ii) rats monolaterally infused with NMDA into the caudate nucleus; and (iii) gerbils subjected to transient global ischemia. We have compared the activity of LY367385 with that of the novel compound (±)-α-thioxantylmethyl-4-carboxyphenylglycine (LY367366), which antagonizes both mGlu1a and -5 receptors at low micromolar concentrations, but also recruits other subtypes at higher concentrations. Although LY367366 was neuroprotective, it was in general less efficacious than LY357385, suggesting that inhibition of mGlu1 receptors is sufficient to confer significant neuroprotection. We conclude that endogenous activation of mGlu1a receptors (or perhaps other mGlu1 receptor splice variants) contributes to the development of neuronal degeneration of excitotoxic origin.

Original languageEnglish
Pages (from-to)199-207
Number of pages9
JournalNeuropharmacology
Volume38
Issue number2
DOIs
Publication statusPublished - Feb 1999

Fingerprint

alpha-methyl-4-carboxyphenylglycine
alpha-thioxantylmethyl-4-carboxyphenylglycine
Excitatory Amino Acid Antagonists
N-Methylaspartate
Metabotropic Glutamate Receptors
Gerbillinae
Caudate Nucleus
Ischemia
metabotropic glutamate receptor 2

Keywords

  • Global ischemia
  • Group-I metabotropic glutamate receptors
  • LY367366
  • LY367385
  • N-methyl-D-aspartate toxicity
  • Neuroprotection

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

Cite this

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title = "Neuroprotective activity of the potent and selective mGlula metabotropic glutamate receptor antagonist, (+)-2-methyl-4 carboxyphenylglycine (LY367385): Comparison with LY357366, a broader spectrum antagonist with equal affinity for mGlula and mGlu5 receptors",
abstract = "(+)-2-Methyl-4-carboxyphenylglycine (LY367385), a potent and selective antagonist of mGlu1a metabotropic glutamate receptors, was neuroprotective in the following in vitro and in vivo models of excitotoxic death: (i) mixed cultures of murine cortical cells transiently exposed to N-methyl-D-aspartate (NMDA); (ii) rats monolaterally infused with NMDA into the caudate nucleus; and (iii) gerbils subjected to transient global ischemia. We have compared the activity of LY367385 with that of the novel compound (±)-α-thioxantylmethyl-4-carboxyphenylglycine (LY367366), which antagonizes both mGlu1a and -5 receptors at low micromolar concentrations, but also recruits other subtypes at higher concentrations. Although LY367366 was neuroprotective, it was in general less efficacious than LY357385, suggesting that inhibition of mGlu1 receptors is sufficient to confer significant neuroprotection. We conclude that endogenous activation of mGlu1a receptors (or perhaps other mGlu1 receptor splice variants) contributes to the development of neuronal degeneration of excitotoxic origin.",
keywords = "Global ischemia, Group-I metabotropic glutamate receptors, LY367366, LY367385, N-methyl-D-aspartate toxicity, Neuroprotection",
author = "V. Bruno and G. Battaglia and A. Kingston and O'Neill, {M. J.} and Catania, {M. V.} and {Di Grezia}, R. and F. Nicoletti",
year = "1999",
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T1 - Neuroprotective activity of the potent and selective mGlula metabotropic glutamate receptor antagonist, (+)-2-methyl-4 carboxyphenylglycine (LY367385)

T2 - Comparison with LY357366, a broader spectrum antagonist with equal affinity for mGlula and mGlu5 receptors

AU - Bruno, V.

AU - Battaglia, G.

AU - Kingston, A.

AU - O'Neill, M. J.

AU - Catania, M. V.

AU - Di Grezia, R.

AU - Nicoletti, F.

PY - 1999/2

Y1 - 1999/2

N2 - (+)-2-Methyl-4-carboxyphenylglycine (LY367385), a potent and selective antagonist of mGlu1a metabotropic glutamate receptors, was neuroprotective in the following in vitro and in vivo models of excitotoxic death: (i) mixed cultures of murine cortical cells transiently exposed to N-methyl-D-aspartate (NMDA); (ii) rats monolaterally infused with NMDA into the caudate nucleus; and (iii) gerbils subjected to transient global ischemia. We have compared the activity of LY367385 with that of the novel compound (±)-α-thioxantylmethyl-4-carboxyphenylglycine (LY367366), which antagonizes both mGlu1a and -5 receptors at low micromolar concentrations, but also recruits other subtypes at higher concentrations. Although LY367366 was neuroprotective, it was in general less efficacious than LY357385, suggesting that inhibition of mGlu1 receptors is sufficient to confer significant neuroprotection. We conclude that endogenous activation of mGlu1a receptors (or perhaps other mGlu1 receptor splice variants) contributes to the development of neuronal degeneration of excitotoxic origin.

AB - (+)-2-Methyl-4-carboxyphenylglycine (LY367385), a potent and selective antagonist of mGlu1a metabotropic glutamate receptors, was neuroprotective in the following in vitro and in vivo models of excitotoxic death: (i) mixed cultures of murine cortical cells transiently exposed to N-methyl-D-aspartate (NMDA); (ii) rats monolaterally infused with NMDA into the caudate nucleus; and (iii) gerbils subjected to transient global ischemia. We have compared the activity of LY367385 with that of the novel compound (±)-α-thioxantylmethyl-4-carboxyphenylglycine (LY367366), which antagonizes both mGlu1a and -5 receptors at low micromolar concentrations, but also recruits other subtypes at higher concentrations. Although LY367366 was neuroprotective, it was in general less efficacious than LY357385, suggesting that inhibition of mGlu1 receptors is sufficient to confer significant neuroprotection. We conclude that endogenous activation of mGlu1a receptors (or perhaps other mGlu1 receptor splice variants) contributes to the development of neuronal degeneration of excitotoxic origin.

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