TY - JOUR T1 - Antagonist Pharmacology of Metabotropic Glutamate Receptors Coupled to Phospholipase D Activation in Adult Rat Hippocampus: Focus on (2<em>R</em>,1′<em>S</em>,2′<em>R</em>,3′<em>S</em>)-2-(2′-Carboxy-3′-phenylcyclopropyl)glycine Versus 3,5-Dihydroxyphenylglycine JF - Molecular Pharmacology JO - Mol Pharmacol SP - 699 LP - 707 VL - 55 IS - 4 AU - Serenella Albani-Torregrossa AU - Sabina Attucci AU - Maura Marinozzi AU - Roberto Pellicciari AU - Flavio Moroni AU - Domenico E. Pellegrini-Giampietro Y1 - 1999/04/01 UR - http://molpharm.aspetjournals.org/content/55/4/699.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -