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Molecular Pharmacology

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Research ArticleArticle

Antagonist Pharmacology of Metabotropic Glutamate Receptors Coupled to Phospholipase D Activation in Adult Rat Hippocampus: Focus on (2R,1′S,2′R,3′S)-2-(2′-Carboxy-3′-phenylcyclopropyl)glycine Versus 3,5-Dihydroxyphenylglycine

Serenella Albani-Torregrossa, Sabina Attucci, Maura Marinozzi, Roberto Pellicciari, Flavio Moroni and Domenico E. Pellegrini-Giampietro
Molecular Pharmacology April 1999, 55 (4) 699-707;
Serenella Albani-Torregrossa
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Sabina Attucci
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Maura Marinozzi
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Roberto Pellicciari
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Flavio Moroni
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Domenico E. Pellegrini-Giampietro
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Abstract

Metabotropic glutamate (mGlu) receptors coupled to phospholipase D (PLD) appear to be distinct from any known mGlu receptor subtype linked to phospholipase C or adenylyl cyclase. The availability of antagonists is necessary for understanding the role of these receptors in the central nervous system, but selective ligands have not yet been identified. In a previous report, we observed that 3,5-dihydroxyphenylglycine (3,5-DHPG) inhibits the PLD response induced by (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate in adult rat hippocampal slices. We now show that the antagonist action of 3,5-DHPG (IC50 = 70 μM) was noncompetitive in nature and nonselective, because the drug was also able to reduce PLD activation elicited by 100 μM norepinephrine and 1 mM histamine. In the search for a selective and more potent antagonist, we examined the effects of sixteen stereoisomers of 2-(2′-carboxy-3′-phenylcyclopropyl)glycine (PCCG) on the PLD-specific transphosphatidylation reaction resulting in the formation of [3H]phosphatidylethanol. The (2R,1′S,2′R,3′S)-PCCG stereoisomer (PCCG-13) antagonized the formation of [3H]phosphatidylethanol induced by 100 μM (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate in a dose-dependent manner and with a much lower IC50 value (25 nM) compared with 3,5-DHPG. In addition, increasing concentrations of PCCG-13 were able to shift to the right the agonist dose-response curve but had no effect when tested on other receptors coupled to PLD. The potent, selective, and competitive antagonist PCCG-13 may represent an important tool for elucidating the role of PLD-coupled mGlu receptors in adult hippocampus.

Footnotes

  • Send reprint requests to: Domenico E. Pellegrini-Giampietro, M.D., Ph.D., Dipartimento di Farmacologia Preclinica e Clinica “Mario Aiazzi Mancini,” Università di Firenze, Viale G. Pieraccini, 6, I-50139 Firenze, Italy. E-maildompel{at}server1.pharm.unifi.it

  • This work was supported by the University of Florence and the European Community (Biomed 2 Project BMH4-CT96-0228 and Biotechnology Project BIO4-CT96-0049).

  • Abbreviations:
    (1S
    3R)-ACPD, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate
    3
    5-DHPG, 3,5-dihydroxyphenylglycine
    iGlu
    ionotropic glutamate
    IP
    inositol phosphate
    L-CCG-I
    l(2S,1′S,2′S)-(carboxycyclopropyl)glycine
    (+)-MCPG
    (+)-α-methyl-4-carboxyphenylglycine
    mGlu
    metabotropic glutamate
    PCCG
    2-(2′-carboxy-3′-phenylcyclopropyl)glycine
    PEt
    phosphatidylethanol
    PKC
    protein kinase C
    PLC
    phospholipase C
    PLD
    phospholipase D
    • Received January 4, 1999.
    • Accepted January 11, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (4)
Molecular Pharmacology
Vol. 55, Issue 4
1 Apr 1999
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Antagonist Pharmacology of Metabotropic Glutamate Receptors Coupled to Phospholipase D Activation in Adult Rat Hippocampus: Focus on (2R,1′S,2′R,3′S)-2-(2′-Carboxy-3′-phenylcyclopropyl)glycine Versus 3,5-Dihydroxyphenylglycine
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Research ArticleArticle

Antagonist Pharmacology of Metabotropic Glutamate Receptors Coupled to Phospholipase D Activation in Adult Rat Hippocampus: Focus on (2R,1′S,2′R,3′S)-2-(2′-Carboxy-3′-phenylcyclopropyl)glycine Versus 3,5-Dihydroxyphenylglycine

Serenella Albani-Torregrossa, Sabina Attucci, Maura Marinozzi, Roberto Pellicciari, Flavio Moroni and Domenico E. Pellegrini-Giampietro
Molecular Pharmacology April 1, 1999, 55 (4) 699-707;

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Research ArticleArticle

Antagonist Pharmacology of Metabotropic Glutamate Receptors Coupled to Phospholipase D Activation in Adult Rat Hippocampus: Focus on (2R,1′S,2′R,3′S)-2-(2′-Carboxy-3′-phenylcyclopropyl)glycine Versus 3,5-Dihydroxyphenylglycine

Serenella Albani-Torregrossa, Sabina Attucci, Maura Marinozzi, Roberto Pellicciari, Flavio Moroni and Domenico E. Pellegrini-Giampietro
Molecular Pharmacology April 1, 1999, 55 (4) 699-707;
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